HUMC 1612: A Phase I Trial of the Optune NovoTTF-200A System With Concomitant Temozolomide and Bevacizumab in Pediatric Patients With High-grade Glioma
Phase: PHASE1
Conditions: High Grade Glioma, Ependymoma
Sponsor: Hackensack Meridian Health

 
HUMC 1612  
 
A Phase I Trial of the Optune NovoTTF-200A System in Combination with 
Temozolomide and Bevacizumab in Pediatric Patients with High-grade Glioma 
and Ependymoma 
 
IDE: G180211 
IDE Holder: Derek Hanson, MD 
 
Joseph M. Sanzari Children’s Hospital 
Arnold Palmer Hospital for Children 
Principal Investigator: 
Derek Hanson, MD 
Children’s Cancer Institute 
Joseph M. Sanzari Children’s Hospital 
Hackensack University Medical Center 
30 Prospect Ave 
Hackensack, NJ 07601 
Phone: 551-996-5437 
Fax: 201-487-7340 
Email: derek.hanson@hackensackmeridian.org 
Co-investigator: 
Avery Wright, DO 
Arnold Palmer Hospital for Children 
92 W Miller St​
2nd Floor​
Orlando, FL 32806 
Phone 321.841.8588 ​
Fax 321.841.8560 
Email:avery.wright@orlandohealth.com 
  
 
Contact:  
Sherri Mayans, RN, MSN, CPNP 
Research Nurse Coordinator 
Children’s Cancer Institute 
Joseph M. Sanzari Children’s Hospital 
Hackensack University Medical Center 
30 Prospect Ave 
Hackensack, NJ 07601 
Phone: 551-996-2283 
Fax: 201-487-7340 
Email:  
Sherri.mayans@hackensackmeridian.org 
 
Investigational Device Provided by: 
Novocure ​
POB 15022  
MATAM Center  
Haifa, 31905, Israel  
 
 
 
 
 
 
 
 
 
 
 
 
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Version Number:  8.1.1 
 
August 7th, 2023 
 
 
TABLE OF CONTENTS 
 
 
1. 
PROTOCOL 
SUMMARY 
AND 
SCHEMA………………………………………………….3  
2. OBJECTIVESANDSCIENTIFIC AIMS…………………………………………………….5 
3. BACKGROUNDAND RATIONALE………………………………………..………….……5 
4. STUDY DESIGN……………………………………………………………………………..15 
5. ELIGIBILITY CRITERIA………………………………………………………………….19 
6. RECRUITMENT PLAN…………………………………………………………………….23​ 
7. PRE-TREATMENT EVALUATIONS…………………………………………….……….24​  
8. TREATMENT PLAN…………………………………………….………………………….24 
9. DOSE MODIFICATIONS FOR TOXICITY……………………………………………....28 
10. DRUG INFORMATION……………………………………….…………………………..33 
11. 
ELECTRODE 
PLACEMENT 
PROTOCOL 
……………..…………………………..…..40 
12. EVALUATIONS DURING NOVOTTF-200A TREATMENT …...……………………..41 
13. 
SCHEDULE 
OF 
ASSESSMENTS 
………………………………………………………...42 
14. STUDY MONITORING AND DATA COLLECTION …………………………….…...43 
15. SURGICAL GUIDELINES………………..…………………………………..…………..46 
16. NEURORADIOLOGY GUIDELINES ………..……..………………………………..….47 
17. 
ADVERSE 
EVENTS 
……………..…………………..…………….…………………..…..52 
18. ADVERSE EVENT REPORTING ……....……………………….….………………..…..53 
19. STUDY OUTCOME MEASURES …………………..………………………………..…..57 
20. STATISTICAL CONSIDERATIONS ………………….……………………………..…..57 
21. CRITERIA FOR REMOVAL FROM STUDY …………..…………………………..…..58 
22. RISK/BENEFIT ANALYSIS ……………………………….……………………………..58 
23. STUDY MONITORING AND QUALITY ASSESSMENT …….…………………..…...58 
24. 
PROTECTION 
OF 
HUMAN 
SUBJECTS 
………………...……………………………...59 
25. INFORMED CONSENT PROCEDURES…………...…………………….……………..59 
26. REFERENCES……………………………………………………………….……………..59 
 
 
 
 
 
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1. PROTOCOL SUMMARY AND SCHEMA  
 
1.1 SUMMARY 
 
 
Title: 
A Phase I Trial of the Optune NovoTTF-200A System in Combination with 
Temozolomide and Bevacizumab in Pediatric Patients with High-grade 
Glioma and Ependymoma 
Device: 
Optune NovoTTF-200A System 
Study Objectives: 
To determine the safety and tolerability of the Optune NovoTTF-200A 
System when used in combination with temozolomide and bevacizumab in 
pediatric patients with newly-diagnosed and recurrent high-grade gliomas 
and recurrent ependymomas. 
 
. 
Study Design: 
Phase I - Prospective, non-randomized, open label 
Study Hypothesis: 
The hypothesis of this study is that the Optune NovoTTF-200A System is a 
safe and well-tolerated treatment for pediatric patients when used in 
combination with temozolomide and bevacizumab for the treatment of 
high-grade gliomas and ependymomas. 
Sample Size: 
Up to 6 pediatric patients with newly-diagnosed or recurrent high-grade 
glioma or recurrent ependymoma for the phase I safety analysis; Up to 6 
patients for the expansion cohort 
Study Population: 
Patients with a tissue-based diagnosis of newly-diagnosed or recurrent 
high-grade glioma or ependymoma greater than 5 and less than 21 years of 
age, of both genders.  
Primary Endpoint: 
This study’s safety endpoint will assess the safety and tolerability of the 
Optune NovoTTF-200A System when used in combination with 
temozolomide and bevacizumab for the treatment of pediatric high-grade 
glioma and ependymoma. This safety endpoint will be determined using 
the rules of a standard 3+3 phase I study design.   
Secondary Endpoint: 
There are no efficacy endpoints for this study.  However, patients will be 
followed to assess their progression-free and overall survival. While the 
study is not powered to provide an efficacy evaluation, the efficacy data 
gained from this study may be useful in designing future phase II/III 
investigations. 
Device Provided by: 
NovoCure Ltd.  
POB 15022  
MATAM Center  
Haifa, 31905, Israel 
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Sponsor: 
Hackensack University Medical Center 
Children’s Cancer Institute 
Joseph M. Sanzari Children’s Hospital 
Hackensack University Medical Center 
30 Prospect Ave 
Hackensack, NJ 07601 
 
 
 
1.2​PROTOCOL SCHEMA 
 
 
 
 
 
 
 
 
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2.​ OBJECTIVES AND SCIENTIFIC AIMS​
 
2.1 PRIMARY OBJECTIVE 
 
●​ To determine the safety and tolerability of the Optune NovoTTF-200A System when used 
in combination with temozolomide and bevacizumab in pediatric patients with 
newly-diagnosed and recurrent high-grade gliomas and recurrent ependymomas. 
 
2.2 SECONDARY OBJECTIVES 
 
●​ To assess the event-free and overall survival of patients treated on this study protocol to 
aid in the future development of pediatric phase II/III studies using the Optune 
NovoTTF-200A System.​
 
2.3 EXPLORATORY OBJECTIVES 
 
●​ To assess the effects of treatment with the Optune NovoTTF-200A System on pediatric 
brain development. 
 
3.​ BACKGROUND AND RATIONALE 
 
3.1​PEDIATRIC HIGH-GRADE GLIOMA 
 
High-grade gliomas (HGG) are relatively rare forms of pediatric brain tumors, constituting only 
8–12% of primary central nervous system (CNS) tumors in children.1  These tumors include 
astrocytomas of either WHO grade 3 (anaplastic astrocytoma) or grade 4 (glioblastoma 
multiforme) pathology. The management of these tumors involves surgical resection to the extent 
feasible, as well as adjuvant radiation and chemotherapy.  ​
 
Surgery provides insight into histologic diagnosis, but the impact of the extent of resection on 
outcome varies.  Although there is debate about extensive tumor resection in adults, there is 
agreement that the extent of resection is directly related to outcome in children.  Campbell et al 
demonstrated retrospectively a relationship between complete resection and long-term prognosis 
in cases of well-circumscribed hemispheric malignant gliomas in children.2 However, surgery by 
itself rarely cures patients because regional tumor infiltration beyond the primary tumor prevents 
complete resections unless the tumor is confined to polar locations, which is uncommon.   
 
For older children and adults, radiation therapy is the most commonly used treatment for HGG.  
All patients are candidates for RT after surgery, except for very young children where an attempt 
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has been made to eliminate or delay the use of RT because of fears regarding 
neuro-developmental morbidity.  Newer techniques, such as conformal RT, which permit more 
precise treatment to the tumor bed are being investigated to reduce treatment related morbidity. 
 
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Even with these interventions, the prognosis for patients with these tumors is poor, with most 
patients succumbing to their disease within 12–18 months.3 These outcomes are far below what 
has been achieved in the treatment of other pediatric cancers.  As a result, new therapies must be 
investigated to improve clinical outcomes for this population.   
3.2 HISTORICAL TREATMENTS FOR PEDIATRIC HIGH-GRADE GLIOMA 
 
Children with high-grade gliomas continue to have poor outcomes despite multi-modal therapy 
with surgical resection, radiation therapy, and chemotherapy.  While surgical resection has a clear 
benefit and radiation does slightly prolong time to progression, to date, chemotherapy, in 
particular, has had little impact on the survival outcomes of these children.   
 
The Children’s Cancer Group (CCG) conducted the first prospective, randomized study of 
adjuvant chemotherapy in children with high-grade astrocytoma, CCG 943.4 In this study, 58 
patients were randomized following surgery to radiation therapy with or without chemotherapy 
consisting of chloroethyl-cyclohexyl nitrosourea (CCNU), vincristine, (VCR), and prednisone.  
The 5-year EFS for the radiotherapy and chemotherapy group was 46%, compared to 18% for 
the radiotherapy-only group.  In patients with GBM, specifically, and at least a partial resection, 
the 5-year EFS for the combined radiotherapy and chemotherapy group was clearly superior at 
42%, compared to 6% for the radiotherapy-only group (P=0.001).  
 
Study CCG 945 randomized 172 patients to receive an 8-in-1 chemotherapy regimen or the 
CCNU/VCR/prednisone regimen used in CCG943.5 The 8-in-1 regimen showed no improvement 
in patient outcomes when compared to the CCNU/VCR/prednisone regimen. The five-year 
progression-free survival (PFS) and OS were 33% and 39%, respectively for the 8-in-1 group, 
where the CCNU/VCR/prednisone group had a PFS of 26% and an OS of 29%. Of note, the 
patients receiving CCNU/VCR/prednisone in the CCG 945 study did not respond as well as the 
patients receiving the same regimen in the CCG 943 study.  The 5-year PFS in CCG for the 
CCNU/VCR/prednisone arm was 46% vs. 26% for the same regimen in protocol CCG 945.  
 
CCG protocol 9933 studied three different high-dose chemotherapy regimens prior to radiation.6 
Seventy six patients were enrolled and received four courses of either etoposide with carboplatin, 
or ifosfamide, or cyclophosphamide.  Patients then received radiotherapy followed by CCNU 
and VCR.  The five-year EFS and OS were 8% (±3%) and 24% (±5%), respectively, without any 
difference in response rates between the three regimens.  These high-dose regimens carried a 
significant amount of morbidity with 29% of patients experiencing severe non-hematologic 
toxicities.   
 
The Pediatric Oncology Group (POG) conducted a phase III study which randomized patients to 
either cisplatin and BCNU or VCR and cyclophosphamide prior to radiotherapy. Outcomes of 
this study were poor with a 5-year survival of 20% for the cisplatin/BCNU arm and 5% for the 
VCR/cyclophosphamide arm.7 
 
 
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Children’s Oncology Group study ACNS0126 used temozolomide (TMZ) as a radiosensitizer 
followed by 10 cycles of TMZ (200 mg/m2/day x 5 days of every 28 day cycle). 107 patients 
with a diagnosis of anaplastic astrocytoma (AA), GBM, or gliosarcoma were enrolled. Ninety 
patients were eligible (31 AA, 55 GBM, and 4 other). The three-year EFS and OS were 11% 
(±3%) and 22% (±5%), respectively. Although this study did not demonstrate an improved 
survival rate compared to CCG 945, the study did demonstrate comparable survival with less 
toxicity than in studies utilizing nitrosurea-based regimens. 
 
In a safety and feasibility study, twelve children and young adults 
with newly diagnosed HGG received radiotherapy with bevacizumab 
and temozolomide followed by bevacizumab, irinotecan and 
temozolomide. The most common ≥grade 3 toxicities included 
lymphopenia, neutropenia and leukopenia. Grade 3 hypertension 
occurred in 2 patients. No intracranial hemorrhages occurred. In HGG 
patients, 3-year progression free survival and OS were 33 % and 50 %, 
respectively. The authors concluded that a bevacizumab-based 
regimen is feasible and tolerable in newly diagnosed children and 
young adults with HGG.8 
 
As demonstrated by the results of the multiple studies detailed above, there is currently no 
effective chemotherapy regimen for pediatric high-grade gliomas that can be considered a true 
“standard of care”. Due to its increased tolerability and similar efficacy to nitrosurea-containing 
regimens, temozolomide is currently one of the more common chemotherapy agents used in 
these tumors and has thus been incorporated into the second portion of this study.  Likewise, 
bevacizumab, which also has a relatively favorable side effect profile and is commonly used in 
pediatric high-grade glioma, has been selected as the second standard of care agent. 
Temozolomide and bevacizumab in combination has demonstrated safety and efficacy on par 
with other regimens in both adults and pediatric high-grade glioma studies.8,9 As such, they are 
felt to be reasonable backbone drugs in the second portion of this study combining Optune 
NovoTTF-200A treatment with chemotherapy. 
 
3.3 PEDIATRIC EPENDYMOMA 
 
Ependymoma is the third most common pediatric CNS tumor accounting for 8-10% of all 
diagnoses.10 Unfortunately, outcomes for these tumors are suboptimal with the five-year 
progression-free and overall survival being 50-64% and 23-45%, respectively.11-14 The standard 
of care for ependymoma is maximal feasible surgical resection followed by radiotherapy to the 
primary site. However, the use of radiotherapy in young children remains controversial, 
particularly in those children with supratentorial tumors. Chemotherapy is typically reserved for 
patients with residual tumor post-operatively and administered prior to radiotherapy.15 The 
benefit of post-radiation maintenance chemotherapy is currently being evaluated in the 
Children’s Oncology Group ACNS0831 study.  
 
There is currently no standard of care for recurrent ependymoma in children. Children who 
receive incomplete resections of their tumor are at much higher risk for recurrence than those 
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who receive a gross-total resection. Treatment strategies for children with recurrent ependymoma 
include re-resection and re-irradiation when feasible.16 Chemotherapy has typically not 
demonstrated significant benefit in patients with recurrent tumor.17 There have been documented  
 
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long-term responses to metronomic anti-angiogenic regimens, but these treatments are generally 
not felt to be curative.18,19 Many families of children with recurrent ependymomas seek 
experimental treatment due to the lack of proven therapeutic options. Given the tremendous need 
for investigations of new therapies for children with recurrent ependymoma it is felt that 
including this patient population for enrollment in this phase I study is both reasonable and 
ethical. 
 
3.4 INTRODUCTION TO ELECTRIC FIELDS ​
 
In the laboratory setting and in clinical practice, alternating electric fields show a wide range of 
effects on living tissues. At very low frequencies (under 1 kHz), alternating electric fields 
stimulate excitable tissues through membrane depolarisation.20 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.20,21 In 
addition, low frequency pulsed electric fields have been claimed to stimulate bone growth and 
accelerate fracture healing.22  
 
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.23 This phenomenon serves as the basis for some commonly 
used medical treatment modalities including diathermy and radio frequency tumor ablation, 
which can be applied through insulated electrodes.24  
 
Intermediate frequency electric fields (i.e., tens of kHz to MHz), alternate too fast for causing 
nerve-muscle stimulation and involve only minute dielectric losses (heating). Such fields, of low 
to moderate intensities, are commonly considered to have no biological effect.23 However, a 
number of non-thermal effects, of minor biological consequence, have been reported even at low 
field intensities. These include microscopic particle alignment (i.e., the pearl chain effect25) and 
cell rotation.26, 27 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.28 
 
3.5 NOVOCURE’S TUMOR TREATING ELECTRIC FIELDS (TTFIELDS) ​
 
NovoCure has shown29 that when properly tuned, very low intensity, intermediate frequency 
electric fields (TTFields) stunt the growth of tumor cells. This inhibitory effect was demonstrated 
in all proliferating cell types tested, whereas, non-proliferating cells and tissues were unaffected. 
Interestingly, different cell types showed specific intensity and frequency dependences of 
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TTField inhibition. It has been shown that two main processes occur at the cellular level during 
exposure to TTFields: arrest of proliferation and dividing cell destruction. The damage caused by 
TTFields to these replicating cells was dependent on the orientation of the division process in 
relation to the field vectors, indicating that this effect is non-thermal. Indeed, temperature 
measurements made within culture dishes during treatment and on the skin above treated tumors 
in-vivo, showed no significant elevation in temperature compared to control cultures/mice. Also, 
TTFields caused the dividing cells to orient in the direction of the applied field in a manner 
similar to that described in cultured human corneal epithelial cells exposed to constant electric 
fields.30 At the sub-cellular level it was found that TTFields disrupt the normal 
polymerization-depolymerization process of microtubules during mitosis. Indeed, the described 
abnormal mitotic configurations seen after exposure to TTFields are similar to the morphological 
abnormalities seen in cells treated with agents that interfere directly31, 32 or indirectly33-35 with 
microtubule polymerization (e.g., Taxol).  
 
3.6 MODELING THE MECHANISM OF ACTION OF TTFIELDS  
 
In order to explain how TTFields cause orientation dependent damage to dividing cells and 
disrupt the proper formation of the mitotic spindle NovoCure modeled the forces exerted by 
TTFields on intracellular charges and polar particles using finite element simulations. Two main 
mechanisms by means of which the electric fields may affect dividing cells were recognized. The 
first relates to the field effect on polar macromolecule orientation. Within this framework, during 
the early phases of mitosis, i.e., in pre-telophase, when tubulin polymerization-depolymerization 
drives the proliferation process, the electric field forces any tubulin dimers, positioned further 
than 14nm away from the growing end of a microtubule, to orient in the direction of the field. 
This force moment, (10-5 pN) acting on the dimers, is sufficient to interfere with the proper 
process of assembly and disassembly of microtubules that is essential for chromosome alignment 
and separation.36 This effect can explain the mitotic arrest of TTField treated cells.37  
 
The second mechanism, which interferes with cell division, and is most likely to play an 
important role in cell destruction, becomes dominant during cleavage. As seen in simulations, the 
electric field within quiescent cells is homogenous, whereas the field inside mitotic cells, during 
cytokinesis, is not homogenous. An increased field line concentration (indicating increased field 
intensity) is seen at the furrow, a phenomenon that highly resembles the focusing of a light beam 
by a lens. This in-homogeneity in field intensity exerts a unidirectional electric force, on all 
intracellular charged and polar entities (including induced dipoles), pulling them towards the 
furrow (regardless of field polarity). For example, for a cleavage furrow that reached a diameter 
of 1µm in an external field of only 1 V/cm, the force exerted on the microtubules is in the order 
of 5pN. This magnitude is compatible with the reported forces necessary to stall microtubule 
polymerization which is 4.3 pN.38 With regards to other particles, such as cytoplasmatic 
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 µm/sec. At such velocity, cytoplasmatic 
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  
 
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external field. This is consistent with the dependence of the destructive effect of TTFields on the 
angle between division axis and the field, as demonstrated experimentally. In addition, the 
calculated dependence of the magnitude of this force on frequency is consistent with the 
experimentally determined frequency dependence of the inhibitory effect of TTFields on 
melanoma and glioma cell proliferation (120 kHz vs. 200 kHz, respectively).  
 
3.7 IN VIVO EFFECTS OF TTFIELDS  
 
NovoCure has shown39 that TTFields can be applied effectively to animals through electrodes 
placed on the surface of the body. Using a special type of electrically insulated electrodes, 
significant inhibition of the growth of both intradermal melanoma (B16F1) in mice and 
intracranial glioma (F-98) 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.  
 
Extensive safety studies in healthy rabbits and rats exposed to TTFields for protracted periods of 
time have shown no treatment related side effects. The reasons for the surprisingly low toxicity 
of TTField treatment can be explained in the light of the known passive electric properties of 
normal tissues within the body and the effects of electric fields applied via insulated electrodes. 
More specifically, two types of toxicities may be expected in an electric field based treatment 
modality. First, the fields could interfere with the normal function of excitable tissues within the 
body causing, in extreme cases, cardiac arrhythmias and seizures. However this is not truly a 
concern with TTFields since, as frequencies increase above 1 kHz, excitation by sinusoidal 
electric fields decreases dramatically due to the parallel resistor-capacitor nature of the cell 
membrane (with a time constant of about 1ms). Thus, as expected, in both acute and chronic 
application of TTFields to healthy animals, no evidence of abnormal cardiac rhythms or 
pathologic neurological activity was seen.  
 
Secondly, the anti-mitotic effect of TTFields might be expected to damage the replication of 
rapidly dividing normal cells within the body (bone marrow, small intestine mucosa). 
Surprisingly, no treatment related toxicities were found in any of the animal safety trials 
performed by NovoCure, even when field intensities 3 fold higher than the effective anti-tumoral 
dose were used. The lack of damage to intestinal mucosa in TTField-treated animals is probably 
a reflection of the fact that the small intestine mucosal cells have a slower replication cycle than 
neoplastic cells and that the intestine itself most likely changes its orientation in relation to the 
applied field quite often, lowering the efficacy of TTField mediated mitotic disruption. Bone 
marrow, on the other hand, is naturally protected from TTFields by the high electric resistance of 
both bone and bone marrow compared to most other tissues in the body. To test the later 
assumption, the TTField intensity within the bone marrow of a long bone was modeled using the 
finite element mesh (FEM) method. It was found that the intensity of TTFields was 100-fold 
lower within the bone marrow compared to the surrounding tissues (including within solid 
tumors). Thus, hematopoietic cell replication should not be affected even when TTField 
intensities 10-fold higher than necessary to inhibit tumor growth are applied. 
 
 
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3.8 THE NOVOTTF-200A DEVICE  
 
The NovoTTF-200A device is a portable battery operated device which produces TTFields 
within the human body by means of surface electrodes. The TTFields are applied to the patient 
by means of surface electrodes that are electrically insulated, so that resistively coupled electric 
currents are not delivered to the patient. The electrodes, which incorporate a layer of adhesive 
hydrogel and a layer of hypoallergenic medical tape, are placed on the patient’s shaved head. The 
electrodes must be replaced every three to four days and the scalp re-shaved in order to maintain 
optimal capacitative coupling between the electrodes and the patient head. All the treatment 
parameters are pre-set by NovoCure so there are no electrical output adjustments available to the 
patient. The patient must learn to change and recharge depleted device batteries and to connect to 
an external battery pack overnight.  
 
Of note, the NovoTTF-200A is a second generation device and has received approval by the 
FDA in adults.  The first generation device, the NovoTTF-100A, was used to conduct many of 
the initial clinical trials for the device in adults.  
 
3.9 CLINICAL STUDIES OF NOVOTTF SYSTEM IN ADULT PATIENTS 
 
3.9.1 A PHASE III STUDY OF MAINTENANCE THERAPY WITH 
TUMOR-TREATING FIELDS PLUS TEMOZOLOMIDE VS TEMOZOLOMIDE 
ALONE FOR GLIOBLASTOMA 
 
A phase III study was performed to evaluate the efficacy and safety of TTFields used in 
combination with temozolomide maintenance treatment after chemoradiation therapy for patients 
with glioblastoma. After completion of chemoradiotherapy, patients with glioblastoma were 
randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide 
(n = 466) or temozolomide alone (n = 229). The study enrolled 695 of the planned 700 patients 
between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, 
Israel, and South Korea.  
 
Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays 
placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 
mg/m2/d) was given for 5 days of each 28-day cycle. 
 
The trial was terminated based on the results of this planned interim analysis. The interim 
analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized 
to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 
months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% 
CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 
months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 
0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months 
(95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months 
(95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 
0.42-0.98]; P = .004). 
 
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In this interim analysis of 315 patients with glioblastoma who had completed standard 
chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy 
significantly prolonged progression-free and overall survival. 40 
 
3.9.2 EFFECT OF NOVOTTF-100A ON NEWLY DIAGNOSED GLIOBLASTOMA 
PATIENTS – CLINICAL PILOT STUDY  
 
A pilot study was performed so far on ten newly diagnosed glioblastoma (GBM) patients treated 
with the NovoTTF-100A device. All patients underwent surgery and radiotherapy for the 
primary tumor. All patients received Temozolomide as adjuvant chemotherapy, in addition to 
NovoTTF-100A treatment.  
 
All patients were treated with multiple four-week treatment courses using continuous, 24-hour a 
day, 200 kHz, 0.7 V/cm TTFields. TTFields were applied through two sets of opposing insulated 
electrode arrays and alternated at a 1 second duty cycle between two perpendicular field 
directions through the tumor. Patients completed between 1 and 17 treatment courses leading to 
maximal treatment duration of 16.5 months. Overall, more than 96, 4 week treatment courses 
were completed to date (> 9.6 courses per patient on average).  
 
The treatment was well tolerated with no treatment related serious adverse events seen in any of 
the patients. Patients received treatment on average about 80% of the scheduled time. 
Considering the continuous nature of NovoTTF treatment (i.e., 24 hours a day for many months) 
this figure indicates that compliance with treatment was very high, with patients taking very few 
days off treatment and stopping only for short periods of time during treatment for personal 
needs.  
 
Mild to moderate contact dermatitis appeared beneath the electrode gel in all patients during 
treatment. In most cases this dermatitis appeared for the first time during the second treatment 
course. The skin reaction improved with use of topical corticosteroids. Regular relocation of the 
electrode arrays was necessary in order to allow for continuous treatment.  
 
The median progression free survival (PFS) of the patients in this study exceeded concurrent and 
historical controls41 dramatically (greater than 18 months versus 7.1 months, respectively). = 
Median overall survival from diagnosis was greater than 26 months (compared to 14.6 months in 
historical controls41). 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 the NovoTTF system treatment as an effective therapy for newly diagnosed 
GBM patients. 
 
3.9.3 EFFECT OF NOVOTTF-100A ON RECURRENT GLIOBLASTOMA PATIENTS – 
CLINICAL PILOT STUDY  
 
A pilot study was performed on ten recurrent GBM patients treated with the NovoTTF-100A 
device. All patients underwent surgery and radiotherapy for the primary tumor. Only 1 patient 
was chemotherapy naïve, the rest having received either Temozolomide or other 
chemotherapeutic agents, as adjuvant treatment, prior to recurrence.  
 
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All patients were treated with multiple four-week treatment courses using continuous, 24-hour a 
day, 200 kHz, 0.7 V/cm TTFields. TTFields were applied through two sets of opposing insulated 
electrode arrays and alternated at a 1 second duty cycle between two perpendicular field 
directions through the tumor. Patients completed between 1 and 15 treatment courses leading to 
maximal treatment duration of 14.5 months. Overall, more than 70, 4-week treatment courses 
were completed to date (> 7 courses per patient on average).  
 
The treatment was well tolerated with no treatment related serious adverse events seen in any of 
the patients. Patients received treatment on average about three quarters of the scheduled time. 
Considering the continuous nature of NovoTTF treatment (i.e., 24 hours a day for many months) 
this figure indicates that compliance with treatment was very high, with patients taking very few 
days off treatment and stopping only for short periods of time during treatment for personal 
needs.  
 
Mild to moderate contact dermatitis appeared beneath the electrode gel in 8 of the 10 patients 
during treatment. In most cases this dermatitis appeared for the first time during the second 
treatment course. The skin reaction improved with use of topical corticosteroids. Regular 
relocation of the electrode arrays was necessary in order to allow for continuous treatment.  
 
The median progression free survival (PFS) of the patients in this study exceeded historical 
controls2 dramatically (26.1 weeks versus 9 weeks, respectively). The PFS at 6 months (PFS6) 
was 50% compared to 15% in historical controls.42 Median overall survival was 62 weeks. 
Response rate was 25% (1 CR + 1 PR) and only two patients had progressive disease despite 
treatment.  
 
3.9.4 EFFECT OF NOVOTTF-100A ON RECURRENT GLIOBLASTOMA PATIENTS – 
PIVOTAL STUDY ​
 
In a prospective, randomized, open label, active parallel control trial to compare the effectiveness 
and safety outcomes of recurrent GBM subjects treated with NovoTTF-100A (n=120) to those 
treated with an effective best standard of care chemotherapy (including bevacizumab; n=117), 
NovoTTF-100A subjects had comparable overall survival to subjects receiving the best available 
chemotherapy in the US today (OS 6.3 vs. 6.4 months; HR 1.0; p=0.98). Similar results showing 
comparability of NovoTTF-100A to BSC chemotherapy were seen in all secondary endpoints 
(e.g., PFS6 = 21.4% for NovoTTF-100A vs. 15.2% for chemotherapy). 
 
NovoTTF-100A subjects experienced fewer adverse events in general, significantly fewer 
treatment related adverse events, and significantly lower gastrointestinal, hematological and 
infectious adverse events compared to BSC controls. The only device-related adverse events 
seen were a mild to moderate skin irritation beneath the device electrodes, which was easily 
treated with topical ointments. Finally, quality of life measures were better in NovoTTF-100A 
subjects as a group when compared to subjects receiving effective best standard of care 
chemotherapy.  
 
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3.10 CLINICAL STUDIES OF NOVOTTF SYSTEM IN PEDIATRIC PATIENTS 
​
The Pediatric Brain Tumor Consortium study PBTC-048 is an ongoing trial examining the 
feasibility and device-related toxicity of TTFields in children 5–21 years of age with recurrent 
supratentorial HGG and ependymoma.43 Feasibility is defined in this trial as 
the ability of pediatric subjects to wear Optune ≥18 hours/day for at 
least 23/28 days of cycle one.  
 
The study’s planned interim analysis included 11 patients (seven males and four females) with 
supratentorial tumors (ten high-grade glioma and one ependymoma). Ten patients were evaluable 
(one patient had progressive disease during the feasibility period) and four remained on study 
through 4 cycles. One grade 5 intracranial hemorrhage not associated with the device and no 
grade IV toxicities occurred. Three patients had seizures (grade 1–3), fatigue, scalp pain, 
localized rash, and headache (none greater than grade 3). Of the 10 evaluable patients, 7 satisfied 
the feasibility criteria for the Optune therapy, which was above the prespecified threshold of at 
least 6/11. These preliminary results were determined to indicate feasibility of monotherapy with 
Optune in the pediatric population with minimal toxicity.  
 
Quality of life assessments were performed as part of the interim analysis.44 Participating patients 
and one of their parents completed the following measures at baseline and prior to each 
intervention cycle: PROMIS Fatigue, Anger, Anxiety, Depressive Symptoms, Mobility, Upper 
Extremity Function, and Peer Relationships and Neuro-QOL Stigma. Participants also completed 
an exit survey when they were off the study regarding their experiences wearing the device. 
 
Patients reported worse HRQOL than the norms on all domains. Six of eleven patients completed 
the exit survey. No significant changes (p< 0.05) between the baseline and the final assessment 
were found except for Stigma. Patients perceived less stigma at baseline than at the final 
assessment (t=2.82, p=0.0370). Of these 6 parents who completed the exit survey, most 
considered wearing the device to be easy (n=5). Patient reminders were unnecessary (n=5), 
patients rarely/didn’t complain (n=4) or refuse (n=5) to wear the device, there was rare/no (n=4) 
difficulty with daily activities because of the device, and patients were not (n=4) or sometimes 
(n=2) embarrassed to wear the device.  These preliminary results indicate Optune-delivered 
TTFields therapy is feasible and accepted by children and parents with no evidence of negatively 
impacting patients’ quality of life 
 
3.11 STUDY RATIONALE 
 
Pediatric high-grade gliomas are aggressive tumors that carry a poor prognosis.  In the recurrent 
setting, the outcomes for children with ependymomas are equally dismal.  There is currently no 
standard-of-care for these tumors and patients are in desperate need of improved and innovative 
new therapies.  TTFields have proven to be a safe and efficacious approach to the treatment of 
adult high-grade gliomas and the Optune device is currently FDA-approved for this indication. 
Preliminary pediatric investigations have demonstrated the safety and feasibility of delivering 
TTFields to children with high-grade glioma and ependymoma. Given these positive results, 
further exploration into the use of TTFields for pediatric high-grade glioma and ependymoma are 
warranted.   
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TTFields, temozolomide, and bevacizumab each have a track record of tolerability in children 
and have non-overlapping toxicity profiles. Historically, most improvement in pediatric cancer 
outcomes have been achieved with the use of combination therapy. With this in mind, the 
proposed study regimen combining TTFields with the chemotherapy agents temozolomide and 
bevacizumab is felt to be a rational next-step in the investigation of the Optune NovoTTF-200A 
system in children.  
 
4.0​STUDY DESIGN 
 
4.1 PHASE 1 DESIGN 
 
This proposed phase I trial will utilize a standard 3+3 design to determine the safety and 
tolerability of the Optune NovoTTF-200A System in combination with temozolomide and 
bevacizumab in pediatric high-grade glioma and ependymoma patients. The phase I safety 
evaluation period will encompass the first two cycles (56 days) of treatment. If one or fewer 
serious adverse events related to treatment are observed in the first three patients of this cohort, 
then an additional three patients will be enrolled.  If fewer than two adverse events related to 
treatment are noted following the phase I safety evaluation period for all six patients, then the 
study will conclude that treatment with the Optune NovoTTF-200A System in combination with 
temozolomide and bevacizumab is well-tolerated for pediatric patients with high-grade gliomas 
and ependymomas. If at any point two or more patients experience a serious adverse event 
related to treatment, then the study will close.  
 
Once a patient is enrolled it is planned that they will continue to receive treatment in cycles of 28 
days (4 weeks), which may be repeated continuously without therapy interruption for 12 cycles 
or until any criterion for discontinuation (clinical or radiological progression of disease, 
clinically unacceptable toxicity, completion of treatment, etc.) is met. Patients who appear to 
benefit from this treatment will be allowed to continue treatment beyond 12 cycles if approved 
by the study Principle Investigator. 
 
Following the completion of enrollment for the phase I cohort, enrollment will open for an 
expansion cohort of an additional six patients. The expansion cohort will allow for the collection 
of additional safety and efficacy data of the study regimen and also allow eligible patients access 
to TTFields treatment while a phase II protocol is being developed. Patients in the expansion 
cohort will follow the eligibility guidelines and treatment plan as outlined in the protocol.  
 
4.2 TREATMENT PLAN 
 
Enrolled subjects will receive TTField treatment with the Optune NovoTTF-200A system, 
administered at 200kHz for a minimum of 18 hours per day in 28 day cycles. Patients will also 
receive temozolomide 200mg/m2/dose orally on Days 1-5, as well as bevacizumab 10mg/kg/dose 
intravenously on Days 1 and 15 of each 28 day cycle.  Phase I safety evaluation will take place 
over the initial two cycles (56 days) of treatment. Following the completion of the safety 
evaluation period, patients will continue to receive treatment in 28 day cycles, which may be 
repeated continuously without therapy interruption until any criterion for discontinuation is met. 
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4.3.​ CONCOMITANT THERAPY RESTRICTIONS 
 
4.3.1​ No other cancer chemotherapy or immunomodulating agents will be used.​
 
4.3.2​ Filgrastim (G-CSF) may be used at the treating physician’s discretion to enhance 
neutrophil recovery when clinically indicated (e.g., for culture proven bacteremia or 
invasive fungal infection). Routine use of filgrastim in clinically well patients awaiting 
count recovery is not recommended.​
 
4.3.3​ Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary.​
 
4.3.4​ Corticosteroid therapy is permissible only for treatment of increased intracranial pressure. 
The lowest dose consistent with good medical management should be used. Patients 
receiving corticosteroids must be on a stable or decreasing dose prior to study enrollment. 
Corticosteroids should NOT be used as an antiemetic due to their effect on the blood 
brain barrier.  
 
4.4​ DEFINITIONS OF SERIOUS ADVERSE EVENTS 
 
Serious adverse events are based on Version 5.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf.  
 
Serious adverse events are defined as: 
a)​ The development of new seizures or an increase in the grade of seizures based on 
CTCAE 5.0 criteria for those patients with baseline seizures 
c)  Any grade 4 non-hematological toxicity 
d)  Any grade 3 non-hematological toxicity with the specific exception of  
i. Grade 3 nausea and vomiting of less < 5 days duration responsive to 
antiemetic therapy; 
ii. Grade 3 increased alanine aminotransferase (ALT or SGPT) that return to 
levels that meet initial eligibility criteria within 7 days of treatment interruption 
and that do not recur upon study re-challenge with treatment 
iii. Grade 3 fever or infection < 5 days duration. 
iv. Grade 3 hypokalemia, hypophosphatemia, hypocalcemia and/or 
hypomagnesemia responsive to oral supplementation 
e) Any grade 2 non-hematological toxicity that persists for ≥ 7 
days and is considered sufficiently medically significant or 
sufficiently intolerable by patients that it requires treatment 
interruption 
f) Any Grade 2 or higher adverse event requiring interruption of protocol treatment for > 
7 days or which recurs upon treatment re-challenge. 
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g) Skin breakdown or evidence of infection, either of which requires a break in 
NovoTTF-200A treatment greater than 3 days 
 
When a serious adverse events is identified, treatment with Optune NovoTTF- should be 
discontinued until resolution of the toxicity.  Treatment with Optune NovoTTF-200A should then 
be restarted, if felt to be clinically appropriate, by the investigator.  
 
4.4.1  Management of Adverse Events, Serious Adverse Events, and Special Reporting 
Situations 
4.4.2 ​ Adverse events (AE) will be graded according to the CTC AE criteria, version 5.0. CTC 
AE version 5.0 may be downloaded from the CTEP web site (http://ctep.cancer.gov).  
4.4.3​ Grade 3 (non-hematologic) and all higher adverse events will be reported to the Protocol 
Chair within 5 days of the occurrence using the form in except as specified in section 
14.5.3. 
4.4.4​ Grade 4 and grade 5 adverse events specified in the table require expedited 
reporting as detailed below. 
Attribution 
Grade 4 
Grade 5# 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
  
Unrelated 
or 
Unlikely 
  
  
SAE 
Report 
  
Report to Study Chair by 
phone within 24 hours of 
occurrence and by fax or 
email using the form  
within 5 calendar days. 
Possible, 
Probable, 
Definite 
SAE 
Report 
  
SAE 
Report 
SAE 
Report 
​
#This includes all deaths within 30 days of the last dose of treatment with a commercial agent regardless of 
attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial 
agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer 
recurrence must be reported according to the instructions above. 
4.4.5 Reporting to Novocure. 
 
In general, the Investigator or study personnel must immediately report to Novocure any 
serious adverse event and Special Reporting Situations, whether or not considered device 
related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the device and the event (e.g., death as a result of anaphylactic 
reaction or fatal hepatic necrosis). In that case, the investigator must immediately report 
the event to Novocure. The sponsor must record non-serious adverse events and report 
them to Novocure according to the timetable for reporting as specified either in the 
protocol or to fulfill regulatory reporting  requirements. 
 
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For each subject, AEs, SAEs, and Special Reporting Situations should be recorded after 
informed consent is obtained until the subject has completed participation in the study as 
follows: 
 
A Serious Adverse Event or Special Reporting Situations must be reported if it occurs 
from the receipt of a signed and dated ICF until 30 days of receiving the study device. 
 
Any serious adverse event or Special Reporting Situation that is ongoing when a subject 
completes his/her participation in the Study must be followed until any of the following 
occurs: 
●​ the event resolves or stabilizes; 
●​ the event returns to baseline condition or value (if a baseline value is available); 
●​ the event can be attributed to agents(s) other than the Study Device, or to factors 
unrelated to Study conduct. 
 
4.4.6 Recording of Adverse Events, Serious Adverse Events and Special Reporting 
Situations​
 
Recording should be done in a concise manner using standard, acceptable medical terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement, if known. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also 
be recorded (a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the 
procedure or surgery is considered an adverse event. Any event requiring in-patient 
hospitalization that occurs during the course of a subject’s participation in a trial must be 
reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are:​
 
A:​
Reasons described in the Protocol, e.g. drug administration, 
Protocol-required testing 
B.​
Surgery or procedure planned prior to entry into the Study. 
 
If, in the Sponsor Investigator’s judgment, a clinical significant worsening from baseline 
is observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), 
angiogram), physical exam finding, or vital sign, a corresponding clinical adverse event 
should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the adverse event, whenever possible.  However, a complete description of 
the signs, symptoms and investigations which led to the diagnosis should be provided. 
For example, if clinically significant elevations of liver function tests are known to be 
secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be 
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recorded. If the cause is not known, the abnormal test or finding should be recorded as an 
adverse event, using appropriate medical terminology (e/g/ thrombocytopenia, peripheral 
edema, QT prolongation). 
 
4.5 PRIMARY EVALUATIONS 
 
During the first two cycles (56 days) of treatment, patients will be closely monitored for adverse 
events related to treatment. They will undergo frequent physical examination and laboratory 
evaluations as needed to assess the safety and tolerability of the treatment regimen. 
 
Patients will be recommended to undergo an MRI scan of the brain with and without contrast 
following the completion of Cycle 2 of treatment to assess the tumor’s response to therapy, and 
then every additional three cycles.  MRI scans may be done more frequently as clinically 
indicated. 
 
4.6 CORE MRI REVIEW ​
 
All MRI scans for study patients will be reviewed by a neuro-radiologist at Hackensack 
University Medical Center or Arnold Palmer Children’s Hospital.  Either digital (DICOM) 
images or analog films can be used for this purpose. Contrast agent and dose per body weight 
must be kept constant between scans for each patient. 
 
5.0​ELIGIBILITY CRITERIA​
 
5.1​INCLUSION CRITERIA​
 
5.1.1​ Age ≥ 5 years and < 22 years​
 
5.1.2​ Patients must have a minimum head circumference of 44 cm​
  
5.1.3​ Diagnosis: 
Patients must have either a histologically- or cytologically-confirmed supratentorial 
high-grade glioma or supratentorial ependymoma.  
 
Patients with metastatic disease involving the infratentorium or spinal cord are eligible 
providing that they have a supratentorial tumor that is able to be targeted with TTFields. 
 
Eligible pathologic diagnoses include: 
 
High-grade Glioma (WHO Grade III or IV):​
Anaplastic Astrocytoma​
Astroblastoma​
Diffuse Midline Glioma​
Glioblastoma​
Gliosarcoma 
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Ependymoma (WHO Grade II or III):​
Ependymoma​
Anaplastic Ependymoma 
Patients with high-grade glioma must be newly-diagnosed or have a tumor that is 
progressive or recurrent following standard treatment. Patients with ependymoma must 
have a tumor that is progressive or recurrent following standard treatment.  
 
5.1.4​ Patients must have received the maximal feasible resection of their tumor and radiation 
therapy (unless contraindicated due to patient age) as part of their initial treatment prior 
to study enrollment.  ​
 
5.1.5​ Timing of therapy​
 
5.1.5.1​Patients must be enrolled before treatment begins.  Treatment must start within 14 
days of study enrollment.​
 
5.1.5.2​All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section.​
 
5.1.5.3​Newly-diagnosed patients must begin therapy within six weeks of the completion 
of radiotherapy, or within six weeks of surgical resection if radiotherapy is 
contraindicated. ​
​
To provide adequate time for study enrollment and initiation of Optune treatment, 
patients in the expansion cohort may receive one cycle (28 days) of treatment 
with temozolomide and bevacizumab prior to beginning therapy with Optune. 
This pre-study cycle of treatment should begin within six weeks of the completion 
of radiotherapy, or within six weeks of surgical resection if radiotherapy is 
contraindicated. Study therapy should then begin within ten weeks of the 
completion of radiotherapy or surgical resection.​
 
5.1.5.4​Recurrent high-grade glioma or ependymoma patients must begin therapy within 
six weeks of documented tumor progression by MRI scan. ​
 
5.1.6​ Patients must have a Lansky or Karnofsky performance status 
score of ≥ 50%, corresponding to ECOG categories of 0, 1 or 2. 
Use Karnofsky for patients > 16 years of age and Lansky for 
patients ≤ 16 years of age. Patients who are unable to walk 
because of paralysis, but who are up in a wheelchair will be 
considered ambulatory for the purpose of assessing the 
performance score.​
 
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5.1.7​ Able to undergo adequate tumor imaging, via magnetic resonance imaging (MRI) scan to 
evaluate disease evolution.​
 
5.1.8​ Adequate hematologic, renal, liver function as demonstrated by laboratory values: ​
 
5.1.8.1​ANC ≥ 1,000/ul 
5.1.8.2​Hemoglobin ≥8.0 gm/dl 
5.1.8.3​Platelet count ≥ 100,000/ul 
5.1.8.4​Adequate Liver Function Defined As  
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, 
and  
• SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. 
5.1.8.5 Adequate Renal Function Defined As Either  
• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2    
• or a serum creatinine less than or equal to the institutional normal for age​
 
5.1.9​ Negative pregnancy test in women of childbearing potential within 7 days of initiating 
investigational therapy​
 
5.1.10​ Recent mothers must agree not to breast feed while receiving medications on study. ​
 
5.1.11​ Patient or legal guardian must give written, informed consent or assent (when applicable).​
 
5.1.12​ Able to swallow and ingest oral medication or have a NG or G-tube for drug 
administration​
 
5.1.13​ Urine protein should be screened by urine analysis. If protein ≥ 
2+ on urinalysis, then Urine Protein Creatinine (UPC) ratio 
should be calculated. If UPC ratio > 0.5, 24-hour urine protein 
should be obtained and the level should be < 1000 mg for patient 
enrollment.​
​
Note: UPC ratio of spot urine is an estimation of the 24 urine 
protein excretion – a UPC ratio of 1 is roughly equivalent to a 
24-hour urine protein of 1000 mg. UPC ratio is calculated using 
one of the following formula:​
 
- [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 
 
5.1.14 Adequate Coagulation Defined As​
 
- PT/INR ≤ 1.5 x upper limit of normal 
 
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5.2​EXCLUSION CRITERIA​
 
5.2.1​ Age <5 years or ≥ 21 years​
 
5.2.2​ Head circumference < 44 cm​
 
5.2.3​ Absence of supratentorial tumor.​
 
5.2.4​ Use of any other investigational drug within five half-lives of that drug prior to the 
initiation of protocol therapy 
 
5.2.5​ Anti-cancer therapy within 4 weeks prior to the initiation of protocol therapy (6 weeks for 
mitomycin and nitrosureas, 4 weeks for curative-intent radiotherapy, and 2 weeks for 
palliative radiotherapy)​
 
5.2.6​ Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events 
(CTCAE version 5.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that 
could impact on safety outcome assessment​
 
5.2.7​ Any surgery within 14 days prior to initiation of protocol therapy (excluding shunt or line 
insertion)​
 
5.2.8​ Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other 
implanted electronic devices in the brain, or documented clinically significant 
arrhythmias. ​
 
5.2.9​  Evidence of increased intracranial pressure (clinically significant papilledema, vomiting 
and nausea or reduced level of consciousness). Patients receiving escalating doses of 
corticosteroids to control symptoms of increased intracranial pressure (e.g., require a 
stable or decreasing dose of corticosteroids for at least 7 days prior to enrollment) will 
also be excluded.​
 
5.2.10​ Known > Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan 
within the last 1 month. Patients with resolving hemorrhage changes, punctate 
hemorrhage or hemosiderin may enter the study ​
 
5.2.11​ Pregnant female patients are not eligible for this study. Pregnancy tests with a negative 
result must be obtained in all post-menarchal females.​
 
5.2.12​ Lactating females must agree they will not breastfeed a child while on this study.​
 
5.2.13​ Males and females of reproductive potential may not participate unless they agree to use 
an effective contraceptive method and continue to do so for at least 6 months after the 
completion of therapy.​
 
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5.2.14​ Any serious and/or unstable pre-existing medical, psychiatric or other condition which in 
the Investigator’s opinion could interfere with subject safety, obtaining written informed 
consent, or compliance with the study protocol​
 
5.2.15​ Known hypersensitivity to temozolomide or bevacizumab​
 
5.2.16​ Patients who are unable to take oral medications because of significant uncontrolled 
vomiting will be excluded. ​
 
5.2.17​ Patients must not have a history of myocardial infarction, severe or unstable angina, 
clinically significant peripheral vascular disease, Grade 2 or greater heart failure, or 
serious and inadequately controlled cardiac arrhythmia.​
 
5.2.18​ Patients must not have a known clinically significant bleeding diathesis or coagulopathy​
 
5.2.19​ Patients who have experienced arterial thromboembolic events, including transient 
ischemic attacks or cerebrovascular accidents are excluded from participation.​
 
 
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5.2.20​ Patients must not have been previously diagnosed with a deep venous thrombosis 
(including pulmonary embolism) and must not have a known thrombophilic condition 
(e.g., protein S, protein C, antithrombin III deficiency, Factor V Leiden or Factor II 
G202`0A mutation, homocysteinemia, or antiphospholipid antibody syndrome).​
 
5.2.21​ Patients must not have a history of an abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within the last 6 months prior to study entry.   ​
 
5.2.22​ Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for 
this study.​
 
5.2.23​ Patients with a history of allergic reaction to Chinese hamster ovary cell products, or 
other recombinant human antibodies are ineligible. 
 
6.0​RECRUITMENT PLAN 
 
6.1 PATIENT POPULATION 
​
The initial cohort of patients will include children (≥ 5 years of age 
and <21 years of age) with newly-diagnosed or recurrent 
supratentorial high-grade gliomas (either WHO Grade III anaplastic 
astrocytoma or WHO Grade IV glioblastoma multiforme) or recurrent 
supratentorial ependymomas (either WHO Grade II ependymoma or WHO Grade III anaplastic 
ependymoma).   
 
6.2 PATIENT SELECTION​
 
Patients will primarily be accrued from the pediatric brain tumor population treated at and 
referred to Hackensack University Medical Center as well as Arnold Palmer Children’s Hospital. 
While the lower age limit for this study is 5 years of age, the patient’s head circumference will 
need to meet the minimum requirement of 44 cm for the Optune NovoTTF-200A device.  
 
Patients will be expected to have received the maximal feasible resection of their tumor and 
radiation therapy (unless contraindicated due to patient age) as part of their initial treatment prior 
to study enrollment.   
 
Newly-diagnosed patients must begin therapy within six weeks of the completion of 
radiotherapy, or within six weeks of surgical resection if radiotherapy is contraindicated. 
Recurrent patients must begin therapy within six weeks of documented tumor progression by 
MRI scan.  
 
There is no prior therapy restriction for recurrent high-grade glioma or ependymoma patients 
receiving treatment with the Optune NovoTTF-200A System.  
 
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Patients will be screened for acceptable performance status and bone marrow and organ function 
prior to enrollment.  Females of childbearing age will receive pregnancy screening prior to 
enrollment. 
 
7.0 PRE-TREATMENT EVALUATIONS 
 
Within one week prior to beginning treatment all patients will undergo the following studies: 
 
●​ Baseline contrast enhanced MRI of the brain (within 6 weeks of beginning treatment).  
●​ Complete physical examination  
●​ Neurological status exam 
●​ Performance Status (Lansky or Karnofsky)  
●​ Complete blood count (CBC) and differential  
●​ Biochemistry panel (Electrolytes, BUN, creatinine, bilirubin, liver enzymes, albumin, 
total protein, glucose)  
●​ Coagulation study (PTT, INR)  
●​ Urinalysis (See Section 5.1.13) 
 
8.0 TREATMENT PLAN 
 
All patients will begin treatment with NovoTTF-200A within 7 days from screening/baseline 
evaluation (See Section 7.0). Newly-diagnosed high-grade glioma patients must begin therapy 
within six weeks of the completion of radiotherapy, or within six weeks of surgical resection if 
radiotherapy is contraindicated. Recurrent high-grade glioma and ependymoma patients must 
begin therapy within six weeks of documented tumor progression by MRI scan.  
 
Patients will report weekly during Cycle 1 of treatment and bi-weekly during Cycle 2 and 
subsequent cycles to the outpatient clinic where they will be assessed clinically and undergo 
routine laboratory examinations. . The follow-up window for these visits is +/- 3 days if the visit 
occurs prior to the 6 month follow-up window and +/- 7 days on or after the 6 month visit 
window..  
 
Criteria to start Cycle 2 and subsequent cycles include: 
●​ Peripheral absolute neutrophil count (ANC) ≥ 1000/µl 
●​ Platelet Count > 100,000/µl (without transfusion within the last 7 days) 
●​ Serum creatinine ≤ 1.5 x normal for age 
●​ Total bilirubin ≤ 1.5 x normal for age, and SGPT (ALT) < 2.5 x 
normal for age 
●​ Urinalysis demonstrating < 2+ protein 
●​ The patient has no evidence of progressive disease as assessed clinically and/or by 
imaging studies 
●​ The patient did not experience a bevacizumab-related targeted toxicity that requires 
discontinuation or withholding of bevacizumab as listed in Section 9.3 
 
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If a patient does not meet criteria to begin a cycle of treatment, treatment with Optune 
NovoTTF-200A may continue.  Temozolomide and bevacizumab administration should be held 
until the patient meets criteria to begin the next cycle. 
 
 
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8.1 OPTUNE NOVOTTF-200A SYSTEM TREATMENT 
 
The NovoTTF-200A treatment will be initiated in an outpatient clinic by the investigator at each 
center. In addition to clinical evaluation (see Section 7.0), the investigator will perform the 
following actions for patients: ​
 
●​ Train the patient in using the device:  
●​ Battery replacement and recharging  
●​ Turning the device on and off  
●​ Disconnecting and reconnecting the electrodes from the device for personal needs  
●​ How to handle device error messages (see trouble shooting section in User 
manual)  
●​ Adverse events that can be expected during the treatment  
●​ How to handle irritated skin  
●​ What to do in case of new or worsening clinical signs (call investigator)  
●​ Review of the baseline MRI and decide where to place the electrodes (according to the 
guidelines elaborated in Section 11.0 below).  
●​ Shave the patients scalp (can be performed by other medical staff in the hospital or by a 
barber prior to coming to the hospital)  
●​ Place the electrodes  
●​ Connect the electrodes to the device (through the connection cable)  
●​ Turn on the device  
 
The device will be set in advance by a device technician with the following treatment 
parameters:  
●​ Frequency – 200 kHz  
●​ Output current – 707 mA RMS  
●​ Number of field directions – 2  
●​ Duty cycle – 1 sec in each direction  
 
The patients will continue treatment at home after being trained in device use.  
 
The treatment group patients will receive 12  28-day courses of continuous NovoTTF-200A 
treatment. The decision to add each additional treatment course will depend on the lack of 
treatment related serious adverse events which reappear upon re-challenge and lack of clinical 
disease progression. Patients who appear to benefit from this treatment will be allowed to 
continue treatment beyond 12 cycles if approved by the study Principle Investigator. 
 
Periodic electrode replacement (twice per week) – patients will be trained to replace electrodes 
independently. Electrodes will be placed in the same locations every time, according to the 
locations originally decided upon by the investigator unless the patient experiences skin 
irritation, in which case, they are alternated (see Section 12.0 below).  
 
 
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The following actions are performed by the technician: 
●​ Periodic download of device log (once every 2 weeks)  
●​ Replacement of faulty equipment  
●​ Device, electrode and accessory accountability tracking, and requests for replacements 
from NovoCure  
●​ Problem solving – by phone between visits to the technical clinic or directly during these 
visits  
●​ For technical support the patient will contact the local technical clinic. A list of clinics 
and their contact information will be supplied to the patients separately. If the patient is 
unable to get a hold of the local device technician or if the patient has technical problems 
with the device beyond working hours he/she should call the following Toll free number 
for NovoCure's international support center: 011 - 800 NOVOCURE. 
 
During NovoTTF-200A treatment the patient will be permitted to interrupt treatment for periods 
that should not, in total, exceed six hours per day (resulting in a minimum of 18 hours of 
treatment per day) for personal needs. Any pause in treatment beyond this must be coordinated in 
advance with the principal investigator or one of the co-investigators. Patients will be 
encouraged to minimize treatment interruptions as the adult study data suggests that treatment 
exposures of more than 18 hours per day correlated with improved outcomes. Patients will be 
allowed an additional 1-3 days off treatment between courses according to personal needs.  
 
8.2 TEMOZOLOMIDE TREATMENT 
 
Dose: 200 mg/m2/day 
 
Administration: Given daily by mouth on Days 1, 2, 3, 4, and 5 of each cycle. 
 
If a patient vomits within 30 minutes after the dose of temozolomide is administered and the 
capsule is visible, that dose should be repeated. If a patient vomits after 30 minutes, the dose will 
not be repeated. Patients who have taken a suspension of temozolomide should not be redosed. 
 
8.3 BEVACIZUMAB TREATMENT 
 
Dose: 10 mg/kg/dose 
 
Days: Given intravenously over 90 Minutes on Days 1 and 15 of each cycle. A platelet count of 
75,000/μL, with or without platelet transfusion, is required to administer bevacizumab.  
 
Note: Infuse first dose over 90 minutes. If tolerated without infusion-related side effects, the 
second dose may be given over 60 minutes. If tolerated, may shorten subsequent infusions to 30 
minutes.  Check vital signs prior to infusion and monitor for infusion-related reactions every 30 
minutes and at the end of the infusion. Monitor every 15 minutes while the infusion rate is being 
adjusted. Routine premedication is not required for the first dose of bevacizumab. If infusion 
reactions occur, acetaminophen [10-15 mg/kg (max 650 mg)], diphenhydramine [1 mg/kg (max  
 
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50 mg)], or other medications may be given for symptom control and for premedication as 
needed. (See Section 4.3 for concomitant therapy restrictions.) Anaphylactic precautions should 
be observed during bevacizumab administration. If an infusion reaction occurs, subsequent doses 
of bevacizumab should be administered over the shortest period that was well-tolerated. 
Bevacizumab is incompatible with D5W (the drug is inactivated). 
 
Special precautions: Black box warning includes risk of gastrointestinal perforation and wound 
healing complications (fatal results have occurred). Suspend dosing at least 28 days prior to 
elective surgery. Do not initiate bevacizumab for at least 28 days after a major surgery (e.g., 
organ resection, exploratory laparotomy, thoracotomy) or 14 days after intermediate surgical 
procedure (e.g., paracentesis or thoracocentesis) and until the surgical wound is fully healed. 
Minor surgical procedures (e.g., biopsies, infusaport, or Broviac line placement) need to have 
fully healed and occurred > 7 days prior to initiation of bevacizumab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4 THERAPY DELIVERY MAP 
Treatment is given in cycles. Each cycle lasts 28 days.  
Use a copy of this page once for each cycle. (Please note cycle number below.) 
This Therapy Delivery Map is on one (1) page 
___________________​
Patient Name 
______________________ 
DOB 
​
Criteria to start cycle 1: ANC ≥1000/µl, platelets > 100,000/µl (transfusion independent), serum creatinine 
≤1.5 x normal for age , total bilirubin ≤1.5 x normal for age, and SGPT (ALT) < 2.5 x normal for age. ​
Criteria to start cycles 2 through 12: ANC ≥1000/µl, platelets > 100,000/µl (transfusion independent), serum 
creatinine ≤ 1.5 x normal for age, total bilirubin ≤ 1.5 x normal for age, SGPT (ALT) < 2.5 x normal for 
age, no bevacizumab-related targeted toxicity that requires discontinuation or withholding of 
bevacizumab as listed in Section 9.3, and no progressive disease. ​
 
Drug 
Route 
Dose 
Days 
Important Notes 
Observations 
Bevacizumab​
(BEVA) 
IV over 90 
minutes* 
10 mg/kg/dose 
Days 1 
and 15 
*Second infusion may be 
given over shorter 
duration if well tolerated. 
See admin. guidelines 
in Section 8.3. 
a.​Hx/PE, Performance 
status 
b.​CBC/diff/platelets 
c.​ BUN/Creatinine/AST/ ​
ALT/bilirubin 
d.​Electrolytes (Ca++, 
PO4, Mg++) 
e.​Urinalysis for Protein 
(urine dipstick or UPC 
ratio) 
f.​ MRI of the Head with 
and without gadolinium 
​
 
Obtain other studies as 
required for good patient 
care 
Temozolomid
e  
(TEM) 
PO 
200 mg/m2 
Days 
1-5   
 
​
Cycle:______    Ht:___________cm    Wt:___________kg    BSA:________m2 
 
Date Due 
Date Given 
Week 
Day 
BEVA 
TEM 
Studies 
Observations​
 
 
 
1 
1 
_____mg 
_____mg 
a, b, c, d, e, f* 
 
 
 
 
2 
 
_____mg 
 
 
 
 
 
3 
 
_____mg 
 
 
 
 
 
4 
 
_____mg 
 
 
 
 
 
5 
 
_____mg 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
2 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
15 
_____mg 
 
a, b, c, d, e 
 
 
 
 
 
 
 
 
 
 
 
4 
22 
 
 
 
 
 
 
 
29 
Begin next cycle on Day 29 or when criteria to begin cycle are met (whichever occurs later). See 
Section 8.1 for end of therapy evaluations. 
Observation Notes: 
* Obtain prior to cycle 1, 3, 6 and then every subsequent 3rd cycle. ​
+ If urine dipstick is 2+ or greater from protein, hold bevacizumab and obtain UPC ratio within 3 days of Day 1 dose of bevacizumab. 
See bevacizumab dose modifications for proteinuria (Section 9.3). If UPC ratio is > 1, collection of 24 hour urine for measurement of urine 
protein level is recommended but not required.​
 
 
 
 
 
 
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9.0 DOSE MODIFICATIONS FOR TOXICITY 
 
The following dose modifications for toxicities are for use during the study. Notify the Study 
Chair at the time of removing a patient from protocol therapy for toxicity. 
 
9.1 HEMATOLOGIC TOXICITY 
 
Every cycle of therapy containing temozolomide should begin when 
ANC  ≥ 1000/µL and platelet count  ≥ 100,000/µL.  If either ANC and/or 
platelet count is lower than the above parameters chemotherapy 
should be held.  Then repeat counts should be drawn a twice weekly 
until counts reach the required levels.  If there is a greater than 2 
week delay in the resumption of temozolomide, then decrease the dose 
of the drug in the previous course by 25%.   
 
9.2 – NON-HEMATOLOGIC TOXICITY​
​
Patients with toxicity attributed to bevacizumab but not listed in Section 9.3 may continue on 
study provided the toxicity is reversible to eligibility requirements within 14 days after the 
planned start of the next treatment course. Patients who have any Grade 3 or 4 non-hematologic 
toxicity that does not resolve to meet starting criteria by 14 days after the planned start of the 
next cycle must be removed from protocol therapy. 
 
9.2.1  Hepatotoxicity 
 
If grade 3-4 toxicity develops, hold chemotherapy until toxicity is less than grade 2.  For the 
purposes of the phase I study, grade 3-4 hepatotoxicity would be considered a dose-limiting 
toxicity. If the etiology of the toxicity is unexplained, then the dose of temozolomide, should be 
reduced by 25%.   
 
9.3 BEVACIZUMAB DOSE MODIFICATIONS 
 
There will be no dose reductions made for toxicity related to bevacizumab. Treatment should be 
interrupted or discontinued for certain adverse events, as described in the table below. If 
bevacizumab is held and a patient cannot resume treatment before the stipulated time for the 
particular toxicity, the patient will be taken off protocol therapy. 
 
 
 
 
 
 
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DOSE MODIFICATIONS FOR BEVACIZUMAB-RELATED ADVERSE EVENTS 
Event  
 CTCAE v 5.0 Grade  
Action to be Taken 
Allergic reactions, 
Or 
Infusion-related reactions 
OR 
Anaphylaxis 
 
Grade 1-2 
Infusion of bevacizumab should be 
interrupted for subjects who develop 
dyspnea or clinically significant 
hypotension.  
 
For infusion-associated symptoms not 
specified above, infusion should be 
slowed to 50% or less or interrupted. 
Upon complete or resolution of the 
symptoms, infusion may be 
continued at no more than 50% of the 
rate prior to the reaction and increased 
in 50% increments every 30 minutes if 
well tolerated. Infusions may be 
restarted at  
the full rate during the next cycle. 
 
If infusional reactions occur,  
acetaminophen [10-15 mg/kg (max 650 
mg)], diphenhydramine [1 mg/kg (max 
50 mg)], or other medications may be 
given for symptom control and for 
premedication as needed. (See Section 
4.2 for concomitant therapy 
restrictions.) 
 
Subjects who experience bronchospasm 
(regardless of grade) should discontinue 
bevacizumab. 
 
Grade 3-4 
Discontinue bevacizumab. 
Thromboembolic Event 
(Arterial); arterial ischemia 
 Cardiac ischemia 
 Myocardial infarction 
 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. 
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Event  
 CTCAE v 5.0 Grade  
Action to be Taken 
Thromboembolic Event 
(Venous) 
Grade 3 
OR 
asymptomatic Grade 4 
Hold bevacizumab treatment. If the 
planned duration of full-dose 
anticoagulation is < 2 weeks, 
bevacizumab should be held until the 
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 not have 
pathological conditions that carry 
high risk of bleeding (e.g. tumor 
involving major vessels or other 
conditions). 
-​  The subject must not have had 
hemorrhagic events while on 
study. 
 
-​ The subject must be on stable dose 
of heparin or have an in-range INR 
(usually 2-3) on a stable dose of 
warfarin prior to restarting 
bevacizumab. 
​
If thromboemboli worsen/recur upon 
resumption of study therapy, 
discontinue bevacizumab. 
Grade 4 
(symptomatic)​
​
 
Discontinue bevacizumab. 
Hypertension* 
Use age and height appropriate 
normal values 
> 95th percentile ULN for pediatric 
patients 
(see Appendices I and II) 
[Treat with anti-hypertensive medication as needed. The goal of BP control should 
be consistent with general medical practice.] 
Grade 1 
If age ≤ 17 years: 
Asymptomatic, transient (< 
24 hrs) BP increase >ULN; 
intervention not indicated.  
If age > 17 years: (SBP 120-139 
mmHg or DBP 80-89 mm Hg) 
Consider increased BP monitoring; start 
antihypertensive medication if 
appropriate 
 
Grade 2 asymptomatic: 
If age ≤ 17 years: Recurrent 
or persistent (≥ 24 hrs) BP > 
ULN; 
If age > 17 years: (SBP 140-159 
mmHg or DBP 90-99 mm Hg) 
If age ≤ 17 years: 
monotherapy indicated 
continue bevacizumab. 
If age > 17 years: Begin anti- 
hypertensive therapy and continue 
bevacizumab. 
 
Grade 2 symptomatic: 
OR 
Grade 3: 
(>17 years: SBP >160mmHg or DBP 
>100mmHg) requiring more than one 
drug or more intensive therapy than 
previously (all ages) 
- Start or adjust anti-hypertensive 
therapy 
- Hold bevacizumab until symptoms 
resolve AND BP < 95th percentile ULN 
for age and height, if age ≤ 
17 years; or 
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BP < 160/90mmHg if age > 17 years. 
 
Grade 4: (all ages) 
life threatening (e.g. hypertensive 
crisis or malignant hypertension) 
Discontinue bevacizumab. 
Event  
 CTCAE v 5.0 Grade  
Action to be Taken 
Heart Failure or LV dysfunction 
Heart failure ≥ grade 2 
LV dysfunction ≥ grade 3 
Discontinue bevacizumab. 
Proteinuria 
Proteinuria will be 
monitored by urine analysis 
for urine protein creatinine 
(UPC) ratio, or dipstick If 
Dipstick ≥ 2+ proteinuria or 
UPC ratio ≥ 1, 24 hour urine 
protein should be obtained 
If 24-h urine protein < 2.0gm 
- Hold bevacizumab until 24-h urine 
protein < 2 gm. 
- Discontinue bevacizumab if urine 
protein does not recover to < 2 after 8 
weeks of bevacizumab interruption 
Grade 4 or nephrotic syndrome 
Discontinue bevacizumab. 
Hemorrhage (intracranial or 
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 or wound 
complications 
Grade 2 
Hold bevacizumab until healing 
Grade 3-4 
Discontinue bevacizumab. 
Perforation (GI or any other organ) 
Discontinue bevacizumab. 
Fistula (GI, pulmonary or any other organ) 
Discontinue bevacizumab. 
Obstruction of GI tract 
Grade 2 requiring medical 
intervention 
 Hold bevacizumab until complete 
resolution. 
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Grade 3-4 
 Hold bevacizumab until complete 
resolution. 
 If surgery is required, patient may 
restart bevacizumab after full recovery  
from surgery, and at investigator’s 
discretion. 
Other Unspecified 
bevacizumab-related AEs 
(except controlled nausea/vomiting). 
Grade 3 
 Hold bevacizumab until symptoms 
resolve 
to ≤ grade 1 
Grade 4 
Discontinue bevacizumab. 
 
9.3.1 GUIDELINES FOR CNS HEMORRHAGE (PUNCTUATE LESIONS) 
 
Definition of punctate hemorrhage identified by neuroimaging: 
 
Punctate hemorrhage on neuroimaging refers to: 
1. Small (< 2mm) foci of presumed hemorrhagic signal within the lesion often demonstrated by 
GRE techniques, without associated mass effect. 
 
2. Curvilinear areas of hemorrhagic signal (< 2 mm thickness) surrounding the lesion, often seen 
with high grade glial tumors. This would include areas identified only on GRE sequences 
(presumably related to hemosiderin deposition). 
 
Patients with punctate hemorrhage will be allowed to continue bevacizumab therapy but will be 
closely monitored for signs and symptoms of worsening hemorrhage. In such an event, repeat 
neuroimaging studies should be obtained including CT scan of head followed by MRI scan of 
brain with GRE sequences. Patients with worsening hemorrhage should be taken off 
bevacizumab. This action would also apply to those who are asymptomatic and are found to have 
worsening hemorrhage on a subsequent routine MRI scan of the brain. 
 
9.3.2 SURGICAL PROCEDURES 
 
Patients may not have had a planned major surgical procedure (such as resection of recurrent 
disease) within 28 days of initiating bevacizumab. If major surgery for local control is planned 
during study therapy for a patient on bevacizumab, then the bevacizumab should be held for one 
cycle prior and for 28 days post definitive resection, unless the patient has had a significant 
post-operative wound complication that, in the opinion of the investigator, would preclude 
bevacizumab administration. In this clinical situation post-operative bevacizumab should be 
withheld for longer. These restrictions are due to concerns of delayed wound healing and 
hemorrhage. Minor surgical procedures (e.g., biopsies, vascular catheter placement, G-tube) need 
to have fully healed and occurred > 7 days prior to initiating bevacizumab. 
 
10.0 DRUG INFORMATION​
 
Drugs are listed in alphabetical order. 
 
10.1 BEVACIZUMAB (rhuMAb VEGF, Avastin®) NSC# 704865 IND # 7921 (11/08/11) 
 
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Source and Pharmacology: 
 
Bevacizumab is a recombinant humanized anti-vascular endothelial growth factor (anti-VEGF) 
monoclonal antibody, consisting of 93% human and 7% murine amino acid sequences. The agent 
is composed of human IgG framework and murine antigen-binding 
complementarity-determining regions. Bevacizumab approximate molecular weight is 149,000 
daltons. Bevacizumab blocks the binding of VEGF to its receptors resulting in inhibition of 
angiogenesis. 
 
The estimated half-life of bevacizumab is approximately 20 days (range 11-50 days). The 
predicted time to reach steady state was 100 days in 491 patients who received 1 to 20 mg/kg 
weekly, every 2 weeks, or every 3 weeks. The clearance and the central volume of distribution 
are higher in males than females. Clearance was higher in those patients with a higher tumor 
volume. 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) For Bevacizumab 
(rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  
 
Adverse Events with Possible Relationship to Bevacizumab (rhuMAb VEGF) 
(CTCAE 5.0 Term) 
Likely (> 20%) 
Less Likely (≤ 20%) 
Rare but Serious (< 3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
●​
Anemia 
●​
Febrile neutropenia 
●​
Blood and lymphatic 
system disorders – Other 
(renal thrombotic 
microangiopathy) 
CARDIAC DISORDERS 
 
●​
Supraventricular 
tachycardia 
●​
Acute coronary syndrome 
●​
Heart failure 
●​
Left ventricular systolic 
dysfunction 
●​
Myocardial infarction 
●​
Ventricular arrhythmia 
●​
Ventricular fibrillation 
​
EAR AND LABYRINTH DISORDERS 
 
●​
Vertigo​
​
​
​
​
​
 
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​
​
​
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​
 
 
 
 
 
 
 
 
 
​
​
 
GASTROINTESTINAL DISORDERS 
 
●​
Abdominal pain 
●​
Colitis 
●​
Constipation 
●​
Diarrhea 
●​
Dyspepsia 
●​
Gastrointestinal 
hemorrhage2 
●​
Gastrointestinal 
obstruction3 
●​
Ileus 
●​
Mucositis oral 
●​
Nausea 
●​
Vomiting 
●​
Gastrointestinal fistula1 
●​
Gastrointestinal 
perforation4 
●​
Gastrointestinal ulcer5 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
●​
Fatigue 
●​
Infusion related reaction 
●​
Non-cardiac chest pain 
●​
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
●​
Allergic reaction 
●​
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
●​
Infection6 
●​
Infections and infestations 
- Other (peri-rectal 
abscess) 
●​
Wound dehiscence 
●​
Gastrointestinal 
anastomotic leak 
INVESTIGATIONS 
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●​
Alanine aminotransferase 
increased 
●​
Alkaline phosphatase 
increased 
●​
Aspartate 
aminotransferase 
increased 
●​
Blood bilirubin increased 
●​
Cardiac troponin I 
increased 
●​
Neutrophil count 
decreased 
●​
Weight loss 
●​
White blood cell 
decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
●​
Anorexia 
 
 
 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
●​
Arthralgia 
●​
Musculoskeletal and 
connective tissue disorder 
- Other (bone metaphyseal 
dysplasia)7 
●​
Myalgia 
●​
Osteonecrosis of jaw8​
​
​
 
 
NERVOUS SYSTEM DISORDERS 
 
●​
Dizziness 
●​
Headache 
●​
Peripheral sensory 
neuropathy9 
●​
Syncope 
●​
Intracranial hemorrhage 
●​
Ischemia cerebrovascular 
●​
Reversible posterior 
Leukoencephalopathy 
syndrome 
RENAL AND URINARY DISORDERS 
 
●​
Hematuria 
●​
Proteinuria 
●​
Acute kidney injury 
●​
Renal and urinary 
disorders – Other 
(Nephrotic Syndrome) 
●​
Urinary fistula 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
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●​
Reproductive system and 
breast disorders - Other 
(ovarian failure)10 
●​
Vaginal hemorrhage 
●​
Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
●​
Allergic rhinitis 
●​
Cough 
●​
Dyspnea 
●​
Epistaxis 
●​
Hoarseness 
●​
Bronchopleural fistula 
●​
Bronchopulmonary 
hemorrhage 
●​
Respiratory, thoracic and 
mediastinal disorders - 
Other (nasal-septal 
perforation) 
●​
Respiratory, thoracic and 
mediastinal disorders - 
Other (tracheoesophageal 
fistula) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
●​
Pruritus 
●​
Rash maculo-papular 
●​
Urticaria 
 
VASCULAR DISORDERS 
●​
Hypertension 
●​
Thromboembolic event 
●​
Vascular disorders – Other 
(arterial thromboembolic 
event)11 
1Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric 
fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC.​
2Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intraabdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC.​
3Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC.​
4Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
5Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
6Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
7Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
8Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
9Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone. 
10Ovarian failure, defined as amenorrhea lasting 3 or more months with 
follicle-stimulating hormone (FSH) elevation (≥30 mIU/mL), was increased in patients 
receiving adjuvant bevacizumab plus mFOLFOX compared to mFOLFOX alone (34% vs. 
2%). After discontinuation of bevacizumab, resumption of menses and an FSH level <30 
mIU/mL was demonstrated in 22% (7/32) of these women. Long term effects of 
bevacizumab exposure on fertility are unknown. 
11Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack, and 
stroke. 
 
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Also reported on Bevacizumab (rhuMAb VEGF) trials but with the relationship to 
Bevacizumab (rhuMAb VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders 
– Other  (idiopathic thrombocytopenia purpura); Disseminated intravascular coagulation 
CARDIAC DISORDERS - Pericardial effusion 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait 
disturbance; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INVESTIGATIONS - Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Musculoskeletal and 
connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective tissue 
disorder – Other (myasthenia gravis) 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral motor neuropathy; Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Pneumonitis; Pneumothorax; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar erythrodysesthesia 
syndrome; Skin ulceration 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
Effect in Pregnancy and Lactation: 
Bevacizumab has been shown to be teratogenic in rabbits when administered in doses that are 
two-fold greater than the recommended human dose on a mg/kg basis. Observed effects included 
decreases in maternal and fetal body weights, an increased number of fetal resorption, and an 
increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were 
observed at all doses tested. Angiogenesis is critical to fetal development and the inhibition of 
angiogenesis following administration of Bevacizumab is likely to result in adverse effects on 
pregnancy. It is not known whether Bevacizumab is secreted in human milk. Because human 
IgG1 is secreted into human milk, the potential for absorption and harm to the infant after 
ingestion is unknown. 
 
Effect on Growth and Development: 
Studies of bevacizumab in animals showed a decrease in ovarian function and abnormal bone 
growth. These and other effects of bevacizumab may potentially impair growth and 
development. Abnormal changes in the bones after treatment with bevacizumab have been 
observed in young children with growing bones. This side effect appeared to be reversible after 
the treatment was stopped, but has not been assessed with long-term use of the drug. 
 
Formulation and Stability: Bevacizumab is supplied as a clear to slightly opalescent, sterile 
liquid ready for parenteral administration. Each 400 mg (25mg/mL, 16 mL fill) glass vial 
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contains bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, 
USP. Upon receipt, refrigerate the intact bevacizumab vials at 2-8°C (36-46°F). Store in the outer 
carton to protect bevacizumab vials from light. Do not freeze. Do not shake. 
 
Bevacizumab vials contain no antibacterial preservatives and are labeled for single use. Discard 
any unused portion left in the vial immediately after use. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
Do not administer as an intravenous (IV) push or bolus. Prior to administration, dilute the dose in 
0.9% sodium chloride for injection to a final concentration of 1.4-16.5 mg/mL. Inspect visually 
for particulate matter and discoloration prior to administration. 
 
The chemical and physical stability of the diluted solution in 0.9% sodium chloride is 48 hours at 
2°C- 30°C. From a microbiological point of view, the product should be used immediately. If not 
used immediately, in-use storage times and conditions are the responsibility of the user and 
would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in 
controlled and validated aseptic conditions. Bevacizumab is incompatible with D5W. 
To ensure complete delivery of bevacizumab IV infusion line must be flushed with 0.9% sodium 
chloride. The following are two recommended methods for flushing the line: 
 
1.​ When the bevacizumab infusion is complete, while maintaining a closed system, add an 
additional 50mL of 0.9% sodium chloride for injection to the bevacizumab infusion bag. 
Continue the infusion until a volume equal to that of the volume contained in the tubing 
has been administered. 
2.​ Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9% sodium chloride 
for injection and infuse a volume equal to the volume contained in the tubing. Please 
note: the flush is not included in the total recommended infusion times. 
 
Supplier: Commercially available. See package insert for further information. 
 
10.2  TEMOZOLOMIDE (Temodar TM) NSC#  362856      (082005)  
 
Source and Pharmacology: An orally administered alkylating agent, a second generation 
imadazotetrazine.  A prodrug of MTIC, temozolomide spontaneously decomposes to MTIC at 
physiologic pH. The drug exerts its effect by cross-linking DNA. This is likely a site specific 
alkylation at the O6-position of guanine with some effect at the N7 position. Temozolomide 
reaches its peak concentration in 1 hour.  Food reduces the rate and extent of absorption.  It has 
an elimination half-life of 1.13hr (intraperitoneally) and 1.29hr (orally) with an oral 
bioavailability of 0.98. Total apparent body clearance is 100ml/min/m2 and plasma elimination 
half-life is ~100 minutes. 
 
Toxicity: 
 
Common 
Happens to 21-100 out of 
every 100 children 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 
100 
Immediate:  
Anorexia,  constipation,  
abdominal pain, diarrhea,  
Convulsions, anaphylaxis,  
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Within 1-2 days of receiving 
drug 
nausea, vomiting 
headache, rash, itching,  
urinary frequency and/or  
infection 
hemiparesis, dizziness, 
ataxia,  
confusion, dysphagia, 
anxiety, thrombo-embolism 
(L) 
Prompt:  
Within 2-3 weeks, prior to 
the next  course 
 Myelosuppression 
Mucositis, lethargy, 
peripheral edema 
Prolonged lymphopenia 
with  
increased risk of infection or 
death, amnesia, insomnia, 
depression, myalgia, 
diplopia, visual changes 
Delayed:  
Any time later during 
therapy 
 
Alopecia, hepatotoxicity 
 
Late:  
Any time after completion 
of  
treatment 
 
 
Secondary tumors or cancer 
Formulation and Stability: 5mg, 20mg, 100mg, 250mg capsules, stored at room temperature 
 
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Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.  
There is a potential for medication errors involving Temodar capsules resulting in drug 
overdosages, which may have been caused by dispensing/taking the wrong number of capsules 
per day and/or product usage exceeding the prescribed dosing schedule. Temodar capsules are 
available in four different strengths, each a different size, and are color coded according to 
strength. All capsules are available in 5-count and 20-count packages. 
 
Capsule Strength​
COLOR  
​
5 mg​ ​
​
Green  Imprint  
​
20 mg​ ​
​
Brown Imprint  
​
100 mg​
​
Blue Imprint  
​
250 mg​
​
Black Imprint 
 
When dispensing, it is extremely important that prescribing and dispensing include clear 
instructions on which capsules, and how many of each capsule(s) are to be taken per day. Only 
dispense what is needed for the course, and clearly indicate how many days of dosing the patient 
will have and how many days are without Temodar dosing. When counseling patients, it is 
important for each patient/parent to understand the number of capsules per day and the number 
of days that they take Temodar. It is also important for the patient/parent to understand the 
number of days that they will be off the medication.   
 
Each strength of Temodar must be dispensed in a separate vial or in its original glass bottle. 
Based on the dose prescribed, determine the number of each strength of Temodar capsules 
needed for the full course as prescribed by the physician. For example, 275 mg/day for 5 days 
would be dispensed as five 250-mg capsules, five 20-mg capsules, and five 5-mg capsules. Label 
each container with the appropriate number of capsules to be taken each day. Dispense to the 
patient/parent, making sure each container lists the strength (mg) per capsule and that he or she 
understands to take the appropriate number of capsules of Temodar from each bottle or vial to 
equal the total daily dose prescribed by the physician. 
 
Supplier:  Commercially available. See package insert for further information   
 
11.0 ELECTRODE PLACEMENT PROTOCOL 
 
The specific locations of each electrode set will be approved by the treating investigator using 
the NovoTAL™ system (Novocure Ltd., Haifa, Israel).  The NovoTal™ system is approved in 
the United States to produce a personalized transducer array layout to maximize the intensity of 
TTFields within the tumor on the basis of morphologic measurements of the head, tumor size, 
and location(s). Personalized treatment planning can result in an almost doubling of field 
intensity directed to the tumor bed in simulation studies. 
 
Initial morphometric head size measurements will be determined from the T1 sequences of the 
patient’s brain MRI, using axial and coronal views. Postcontrast axial and coronal MRI slices 
will be selected to demonstrate the maximal diameter of enhancing lesions. Employing measures 
of head size and distances from predetermined fiducial markers to tumor margins, the  
 
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NovoTAL™ system will run permutations and combinations of paired array layouts in order to 
generate the configuration which will deliver maximal electric field intensity to the tumor site. 
The system will output a three-dimensional array layout map, which will be used by the 
physician and patient in arranging arrays on the scalp during the TTFields therapy. 
 
In a study evaluating physician performance in conducting transducer array layout mapping 
using the NovoTAL System compared with mapping performed by the Novocure in-house 
clinical team, fourteen physicians (7 neuro-oncologists, 4 medical oncologists, and 3 
neurosurgeons) evaluated five blinded cases of recurrent glioblastoma and performed head size 
and tumor location measurements using a standard Digital Imaging and Communications in 
Medicine reader.45 Concordance with Novocure measurement and intra- and inter-rater reliability 
were assessed using relevant correlation coefficients. The study criterion for success was a 
concordance correlation coefficient (CCC) >0.80.  CCC for each physician versus Novocure on 
20 MRI measurements was 0.96 (standard deviation, SD ± 0.03, range 0.90–1.00), indicating 
very high agreement between the two groups. Intra- and inter-rater reliability correlation 
coefficients were similarly high: 0.83 (SD ±0.15, range 0.54–1.00) and 0.80 (SD ±0.18, range 
0.48–1.00), respectively. The study concluded that physicians prescribing TTFields, when 
trained on the NovoTAL System, can independently perform transducer array layout mapping 
required for the initiation and maintenance of patients on TTFields therapy 
 
All electrode mapping for this study will be done by a treating investigator who has been trained 
in NovoTAL™ mapping. In the event that a trained investigator is not available to perform the 
electrode mapping, the patient’s MRI scans will be sent to Novocure for mapping.   
 
12.0 EVALUATIONS DURING NOVOTTF-200A TREATMENT ​
 
During electrode replacement, the skin below the electrode will be inspected by the physician 
(during follow up visits) and by the patient himself or herself (at home or technical center). In the 
event of significant skin breakdown (leading to pain or bleeding) or evidence of infection, the 
electrode will be moved to an alternate site. Skin breakdown and/or infection will be treated 
according to the treating physician’s clinical judgment based on a dermatologist's 
recommendation. ​
​
Skin breakdown or evidence of infection, either of which requires a break in NovoTTF-200A 
treatment greater than 3 days, will be captured as an Adverse Event. ​
​
Mild to moderate contact dermatitis is expected to appear beneath the electrode gel during the 
first or second treatment course. This condition will be treated as follows:  
1. Electrode location will be shifted between two alternate sites at every electrode change.  
2. If skin is inflamed – apply 0.1% hydrocortisone ointment.  
3. If skin is breached (abrasions, micro-ulcerations, oozing, open sores) or infected – Discontinue 
hydrocortisone and prescribe a Mupirocin (e.g. Bactroban) ointment.  
4. In the case of skin blistering – apply Silver Sulfadiazine (e.g. Silverdine ointment). In the case 
of known hypersensitivity to sulfa containing compounds the treatment outlined will not be 
offered and a dermatologist will be consulted.  
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5. In any case where the patient does not notice an improvement in skin sores, infection or 
blistering within 2 weeks of starting one of the treatments outlined above, the patient will inform 
the investigator and a dermatological consult will be obtained.  
6. Oral antihistamines and analgesics will be prescribed at the investigators’ discretion to control 
pruritus and pain.  
 
13.0 SCHEDULE OF ASSESSMENTS​
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable, except where 
explicitly prohibited within the protocol.​
​
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13.1 REQUIRED ASSESSMENTS BEFORE AND DURING PROTOCOL THERAPY 
 
​
 
 
Cycle 
1 
 
 
 
Cycle 
2 
 
 
 
 
 
 
  
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7  
  
Continued 
Therapy 
  
End of Therapy 
/ Progression 
PROCEDURE 
Baseline 
Wk 1 
(D1)  
Wk 2# 
(D8) 
Wk 3 
(D15) 
Wk 4# 
(D22) 
Wk 1 
(D1) 
Wk 3 
(D15) 
Wk 5 
(D29) 
  
Every 2 
Weeks 
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/ 
Exclusion Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Neurological 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
QOL 
Questionnaires5 
 
  
 
 
 
X 
  
 
  
X6 
  
X 
Concomitant 
Meds  
X 
X 
X 
X 
X 
X 
X 
X 
 
X7 
 
X 
LOCAL LABS 
  
  
  
  
  
  
  
  
  
  
  
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Electrolytes, 
BUN, Cr, t.bili, 
AST, ALT ,Ca, 
PO4, Mg 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Urinalysis 1,2 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 RADIOLOGY 
  
  
  
  
  
  
  
  
  
  
  
  
MRI - Brain 3 
X 
  
  
  
  
  
  
X 
  
X* q 3 
months  
  
X 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
Temozolomide 
  
Days 
1-5 
  
  
  
Days 
1-5 
  
  
  
Days 1-5 
  
  
Bevacizumab  
  
Day 1 
  
Day 15 
  
Day 1 
Day 15 
  
  
Days 1 and 
15 
  
  
NovoTTF-200A 
Study Device 4 
  
X 
X 
X 
X 
X 
X 
X 
  
X 
  
  
NovoTTF-200A 
Study Device TX 
Initiation 
 
X 
  
  
  
  
  
  
  
  
  
  
 
OTHER 
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
* screening MRI should be done within 4 weeks of starting study, MRI of the brain is performed at the end of Cycle 2, and then 
routinely q 3 months or if there is a clinical change with signs of progression 
# Cycle 1 Week 2 and Week 4 visits are not required for patients enrolled on the expansion cohort 
Screening/Baseline assessments can be done with Visit 1 prior to administration of chemotherapy and placement of 
electrodes. 
1. Urine protein should be screened by urine analysis. If 2+ on urinalysis, then Urine Protein 
Creatinine (UPC) ratio should be calculated. If UPC ratio > 0.5, 24-hour urine protein should 
be obtained and the level should be < 1000 mg for patient enrollment. See Section 5.1.13 
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regarding calculation of UPC ratio.​
2. If urine dipstick is 2+ or greater from protein, hold bevacizumab and obtain UPC ratio 
within 3 days of Day 1 dose of bevacizumab. See bevacizumab dose modifications for 
proteinuria (Section 9.3). If UPC ratio is ≥ 1, 24 hour urine protein should be obtained.​
3.  MRI with or without sedation​
4. Treatment is administered continuously throughout the study 
5. Patient Questionnaire to be administered to patients aged 8 and above at clinicians’ discretion. All patients will have completed 
parent questionnaires. 
6. Obtain QOL Questionnaires on first day of each cycle beginning with cycle 2 
7. Concomitant medication logs to be maintained on site from 30 days prior to initiation of device through 30 days safety period.  
 
13.2 OPTIONAL ASSESSMENTS BEFORE AND DURING PROTOCOL THERAPY 
 
The effects of TTFields on the developing brain are currently unknown. While this small phase I 
study is not powered or designed to evaluate effects on developmental outcomes from therapy 
with Optune, neuropsychological data from study subjects may provide useful information for 
shaping larger future studies of TTFields in the pediatric population.   
 
Neuropsychological evaluations are routinely performed as part of the standard care for pediatric 
brain tumor patients. Data from the study subject’s routine neuropsychological evaluations will 
be collected and analyzed as part of the exploratory objective of assessing the effects of Optune 
therapy on the developing brain. These neuropsychological evaluations are not required and 
should be ordered at the discretion of the subject’s primary oncologist as per the routine care of 
the study subject. 
 
14.0 STUDY MONITORING AND DATA COLLECTION 
 
14.1 DATA SAFETY MONITORING BOARD (DSMB): 
This study will be monitored by the DSMB at Hackensack University Medical Center, which 
functions independently of all other investigators associated with the conduct of this clinical trial. 
Safety of the investigational device will be assessed on a monthly basis once patients are 
enrolled.  
It is envisioned that the DSMB will make 3 types of recommendations, namely: 
1.​ No safety or ethical issues to continue the study as planned 
2.​ Serious safety concerns precluding further study treatment, regardless of efficacy 
3.​ Recommendation to continue the study but proposing an amendment to the protocol (ex. 
To incorporate additional safety assessments)  
​
14.2 DATA COLLECTION AND MANAGEMENT: 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
1.​ What protected health information (PHI) will be collected from patients in this study 
2.​ Who will have access to that information and why 
3.​ Who will use or disclose that information 
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4.​ The rights of a research patient to revoke their authorization for use of their PHI. 
 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts must 
be made to obtain permission to collect follow-up safety information (e.g., has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
 
Data collected during conduct of the study will be reported to Hackensack University Medical 
Center on Case Report Forms and sent to Study Research Nurse Coordinator via secure email. 
The schedule of form submission is below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.3 DATA FORM SUBMISSION SCHEDULE  
 
DATA FORM SUBMISSION SCHEDULE​
Forms to be submitted to Fax: (201) 968-0518 
Or electronically to:  Sherri.Mayans@hmhn.org 
 
Required Form 
Prior to 
Therapy 
Within 2 Week 
of Study Entry 
After 
Completion of 
Each Cycle 
Comments and 
other details 
Protocol Eligibility Form 
X 
 
 
 
Demographic Form 
X 
 
 
 
Baseline Abnormalities 
X 
 
 
 
Copy of Signed Consent 
Form 
X 
 
 
 
Baseline MRI form (with 
MRI report) 
X 
 
 
 
On Study Form 
 
X 
 
 
Neurosurgical Resection 
Form (with surgical and 
pathology reports) 
 
X 
 
 
Initial (post-op) 
Neuroradiological Form ​
(with post-op imaging 
reports) 
 
X 
 
 
End of Cycle Report Form 
 
 
X 
 
Targeted and Non-targeted 
Toxicity Form 
 
 
X 
 
Adverse Event Form 
 
 
X 
 
MRI follow up form  
 
 
X 
Submit at these 
Intervals: 
​
After cycle 2, then 
every 3months, 
end of therapy 
 
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Parent and Patient1 QOL 
Questionnaires 
 
 
X 
Complete at the 
start of each cycle 
beginning with 
cycle 2  
Serious Adverse Event 
Form 
 
 
 
PRN 
Brain Tumor Relapse 
Form (with imaging 
reports) 
 
 
 
Submit within 10 
days of disease 
progression/relaps
e 
Death Registration Form 
 
 
 
Submit within 10 
days of date of 
death 
1 Patient Questionnaire to be administered to patients aged 8 and above at clinicians’ discretion. All patients will 
have completed parent questionnaires. 
 
14.4 SITE MONITORING: 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, personnel from 
Hackensack University Medical Center or designee will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check the completeness of patient records, the accuracy of entries on the CRFs, the adherence to 
the protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
device is utilized according to specifications.  
 
Key study personnel must be available to assist the field monitor during these visits. The 
investigator must maintain source documents for each patient in the study, consisting of case and 
visit notes (hospital or clinic medical records) containing demographic and medical information, 
laboratory data, electrocardiograms, and the results of any other tests or assessments. All 
information recorded on CRFs must be traceable to source documents in the patient's file. The 
investigator must also keep the original signed informed consent form (a signed copy is given to 
the patient). The investigator must give the monitor access to all relevant source documents to 
confirm their consistency with the CRF entries. Monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan. 
 
The monitor will review the trial sites, either remotely or in person at the following time points: 
1.​ Site initiation visit 
2.​ After enrollment of the first study patient 
3.​ During active enrollment at minimum once a year 
4.​ Study close out 
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Monitor visits will be documented on the Monitoring Site Visit Log that will be provided to sites. 
Query management may be performed via email or separate written document and should be 
filed in the ISF. 
 
 
 
15.0  SURGICAL GUIDELINES 
 
The extent of surgical tumor resection will depend upon the location of the tumor within the 
brain, and its vascularity. Surgical debulking of recurrent tumors should be attempted as 
clinically indicated.   
  
15.1 EXTENT OF RESECTION  
 
Patients will be classified as follows: 
 
Biopsy Only 
An open surgical removal or closed removal of tissue for the purpose of establishing a 
pathological diagnosis, with tumor removal less than 10% of the total tumor mass. 
 
Partial Resection 
Removal of 10% to 49% of the tumor mass. 
 
Subtotal Resection 
Removal of 50% to 90% of the tumor mass. 
 
Radical Subtotal Resection (Near Total) 
Removal of >90% but less than 100% of the tumor mass. 
 
Gross Total Resection 
No visible tumor is left at the time of surgery and this is confirmed by postoperative CT or MRI. 
 
15.2 IMAGING CONFIRMATION OF EXTENT OF RESECTION 
 
See Section 16.0 for Neuroimaging Guidelines. All patients must have confirmation of the 
neurosurgical staging of the extent of resection with a postoperative MRI with and without 
contrast. Post-operative imaging of the brain should be done within 72 hours of surgery if 
possible (preferably within 24 hours of surgery), and prior to the onset of edema or gliosis which 
can make measurements of residual tumor difficult. If imaging cannot be obtained at this time or 
is difficult to interpret, the scan should be repeated 10 or more days after surgery. 
 
15.3 PERI-OPERATIVE CORTICOSTEROIDS 
 
Some patients with large tumors may require initiation of corticosteroid therapy pre-operatively 
to reduce associated cerebral edema or improve neurologic function. Usual corticosteroid dosage 
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is 0.25 to 1 mg/kg/day of, dexamethasone in divided doses every 4-6 hours. Corticosteroids may 
be continued during the peri-operative period; however, every attempt should be made to taper 
and discontinue corticosteroid therapy as soon as clinically feasible. 
 
 
 
 
15.4 SPECIAL PRECAUTIONS FOR BEVACIZUMAB 
 
Black box warning includes risk of gastrointestinal perforation and wound healing complications 
(fatal results have occurred). Suspend dosing at least 28 days prior to elective surgery. Do not 
initiate bevacizumab for at least 28 days after a major surgery (e.g., organ resection, exploratory 
laparotomy, thoracotomy) or 14 days after intermediate surgical procedure (e.g., paracentesis or 
thoracocentesis, ventriculoperitoneal shunt insertion) and until the surgical wound is fully 
healed. Minor surgical procedures (e.g., biopsies, infusaport, or Broviac line placement) need to 
have fully healed and occurred > 7 days prior to initiation of bevacizumab. 
 
16.0 NEURORADIOLOGY GUIDELINES 
 
In order to completely document the assessment of response, the three-dimensional tumor 
measurements for all target lesions upon which the assessments of tumor response are based 
should be explicitly noted in the radiology report for the baseline and all subsequent follow-up 
exams. Reports for the follow-up exams should reiterate the measurements obtained at baseline 
for each target lesion. Non-target lesions or newly occurring lesions should also be enumerated 
in these reports, and changes in non-target lesions should be described. 
 
(Note: all quoted slice thickness is maximal; thinner slices are encouraged, and necessary if the 
lesion imaged is very small) 
 
16.1 WHOLE BRAIN MRI WITH AND WITHOUT CONTRAST 
 
To document the degree of residual tumor, MRI scan with and without contrast, must be done 
prior to starting therapy. Standard 3-dimensional MRI imaging of the head with gadolinium 
should be conducted within six weeks prior to the start of therapy and at the completion of Cycle 
2. Patients who remain on study will continue to undergo MRI imaging every 3 months until the 
end of therapy or documented tumor progression. 
 
Postoperative imaging should be done within 72 hours of surgery, prior to the onset of edema or 
hemorrhage, which can make measurements of residual tumor difficult. If imaging cannot be 
obtained at this time or is difficult to interpret, the scan should be repeated 10 or more days after 
surgery. 
 
1. Sagittal T1 localizer, 5 mm skip 1 mm​
 
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2. Axial T2 and FLAIR 4 mm skip 1 (T2), 5 mm skip 0 (FLAIR) or Axial proton density/T2 if 
FLAIR not available, 5 mm skip 1 mm​
 
3. Optional: Axial T1, 4mm skip 1mm (but highly recommended in post –operative imaging to 
help differentiate post-operative hemorrhage from enhancement)​
 
4. Optional: sagittal or coronal T2 depending on tumor configuration/orientation​
 
5. Post gadolinium axial T1 4mm skip 1mm​
 
6. Post gadolinium coronal/sagittal (at least one, both preferable), 5 mm skip 1​
 
16.2  METHODOLOGY TO DETERMINE TUMOR MEASUREMENT  ​
 
Tumor response criteria are determined by changes in size using all 3 dimensional 
measurements: width (W), transverse (T), and length (L) measurements. Thus for all tumors 
these 3 measurements need to be recorded, using either T1 or T2 weighted images (which ever 
gives the best estimate of tumor size). The following section describes the methodology.  
(See drawing below for illustration) ​
 
1. Longest diameter of target lesion(s) should be selected in the axial plane only for CT. For MRI 
imaging, the longest diameter can be measured from the axial plane or the plane in which the 
tumor is best seen or measured, provided the same plane is used in follow ups. ​
 
2. The longest measurement of the tumor (or width, W) should be determined.  ​
 
3. The 2 perpendicular measurements should be determined (transverse (T) 
measurement-perpendicular to the width in the selected plane, and the length (L) – tumor extent 
in the plane perpendicular to the selected plane)​
 
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TUMOR SIZE MEASUREMENT BASED ON 
CROSS-SECTIONAL IMAGING​
 
• A, B, C, D, & E are contiguous parallel slices in the 
X-Y plane (usually axial) showing the tumor​
​
• W and T are the maximal perpendicular diameters 
on the slice (C in this example) showing the largest 
surface area​
 
• Tumor length in the Z-axis (L) (perpendicular to 
X-Y plane) can be obtained either by the [a] 
(difference 
in table position of the first and last slices showing the 
tumor + one slice thickness), or [b] the product of 
(slice 
thickness + gap) and the number of slices showing the 
tumor 
​
4. The cystic or necrotic components of a tumor are not considered in tumor measurements. 
Therefore only the solid component of cystic/necrotic tumors should be measured. If 
cysts/necrosis compose the majority of the lesion, the lesion may not be “measurable”. Options:​
 
- If the cyst/necrosis is eccentric, the W, T and L of the solid portion should be measured, the 
cyst/necrosis excluded from measurement​
 
- If the cyst/necrosis is central but represents a small portion of the tumor (<25%), disregard and 
measure the whole lesion​
 
- If the cyst/necrosis is central but represents a large portion of the tumor, identify a solid aspect 
of the mass that can be reproducibly measured​
 
5. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured 
accurately. Presence and location of leptomeningeal tumor spread should be noted, change in 
extent/thickness assessed on follow up studies.  
 
6. Overall Response Assessment 
The overall response assessment takes into account response in both target and non-target lesion, 
and the appearance of new lesions, where applicable, according to the criteria described in the 
table below. The overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, and new lesions in the preceding columns. 
 
 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
CR or PR 
Non-PD 
No 
PR 
CR 
Non-PD 
No 
PR 
 SD 
Non-PD 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
CR – Complete Response 
PR – Partial Response 
SD – Stable Disease 
PD – Progressive Disease 
IR – Incomplete Response 
 
The sections that follow discuss the selection and evaluation of each of these types of lesions. 
 
16.3 SELECTION OF TARGET AND NON-TARGET LESIONS 
 
1. For most CNS tumors, only one lesion/mass is present and therefore is considered a “target” 
for measurement/follow up to assess for tumor progression/response. 
 
2. If multiple measurable lesions are present, up to 5 should be selected as “target” lesions. 
Target lesions should be selected on the basis of size and suitability for accurate repeated 
measurements. All other lesions will be followed as non-target lesions.​
 
3. The lower size limit of the target lesion(s) should be at least twice the thickness of the slices 
showing the tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 4 mm slice).​
 
4. Any change in size of non-target lesions should be noted, though does not need to be 
measured.​
 
16.4 RESPONSE CRITERIA FOR TARGET LESIONS​
 
1. Response criteria are assessed in 3 dimensions – the product of LxWxT. An elliptical model 
volume (=0.5LxWxT) is used.​
 
2. To assess response/progression, the ratio is calculated:​
 
LxWxT   (current scan) 
LxWxT (reference scan)​
 
3. Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g. when multiple lesions show 
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opposite responses, the progressive disease takes precedence.​
 
4. Response Criteria for target lesions:​
 
Complete Response (CR): Disappearance of all target lesions.​
 
Partial response (PR): ≥65% decrease in the sum of the products of the 
three perpendicular diameters of all target lesions (up to 5), taking 
as reference the initial baseline measurements.​
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the three 
perpendicular diameters of all target lesions to qualify for PR (taking as reference the initial 
baseline measurements), nor sufficient increase in a single target lesion to qualify for PD, (taking 
as reference the smallest disease measurement since the treatment started). 
 
Progressive Disease (PD): 25% or more increase in the product of perpendicular diameters of 
ANY target lesion, taking as reference the smallest product observed since the start of treatment 
(see exception below), OR the appearance of one or more new lesions, OR worsening neurologic 
status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or 
corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy 
swelling etc.) PLUS any increase in tumor cross-sectional area (or tumor volume).  
 
Exception for Early Progressive Disease 
 
Because both radiotherapy and Optune therapy may be associated with transient, reversible 
swelling, there may be a lag time between the initiation of therapy and maximal anti-tumor 
effect. Removing a patient from protocol therapy as soon as tumor area increases by 25% may 
result in the treatment being terminated prematurely. It is quite possible that if these patients 
were maintained on protocol therapy, their disease might eventually stabilize and even regress. 
 
Therefore, patients will not be considered to have progressive disease and will not be 
removed from protocol therapy for radiographic worsening secondary to local tumor 
enlargement (LTE), defined as increase in maximal bi-dimensional tumor area of 25% or 
more but less than 50%, and with no new lesions on any MRI performed prior to the 
initiation of Cycle 3 treatment. 
 
Thus, prior to the initiation of Cycle 3 therapy, patients should only be removed from protocol 
therapy for progressive disease if there is 50% or more increase in tumor area (with or without 
neurological worsening), OR if there is the appearance of one or more new lesions on the MRI 
outside the radiation port.  
 
The criteria for progressive disease as defined above will commence with all MRI scans 
performed during Cycle 3 onwards. Patients whose tumors meet these criteria will be removed 
from protocol therapy. 
 
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Local progression is defined as progression of known residual tumor or the appearance of tumor 
at known prior sites of disease that were at some point without evidence of disease. Distant 
progression is defined as the appearance of tumor at sites other than known prior sites of disease.  
​
Distant progression most often occurs in the subarachnoid space and may occur at any point 
within the neuraxis. Although rare, extra-CNS metastasis represents distant failure. Combined 
local and distant progression is defined when imaging evaluation reveals local and distant 
progression. 
 
16.5 RESPONSE CRITERIA FOR NON-TARGET LESIONS​
 
Complete Response (CR): Disappearance of all non-target lesions.​
 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or more non-target 
lesions.​
 
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
17.0 ADVERSE EVENTS  
 
17.1 POTENTIAL ADVERSE EVENTS​
 
Treatment with the NovoTTF-200A is not expected to cause any serious side effects. However, it 
is possible that investigational treatment will cause any of the following: ​
 
●​ Local warmth and tingling sensation beneath the electrodes  
●​ Allergic reaction to the plaster or to the gel  
●​ Skin breakdown  
●​ Infection at the sites of electrode contact with the skin  
●​ Electrode overheating leading to pain and/or local skin burns  
●​ Headache  
●​ Fatigue  
●​ Seizures  
 
Treatment with temozolomide commonly (>20%) causes the following adverse events:​
 
●​ Leukopenia  
●​ Headache  
●​ Fatigue  
●​ Nausea  
●​ Vomiting or Constipation  
 
Treatment with bevacizumab commonly (>20%) causes the following adverse events: 
 
●​ Hypertension 
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Adverse events and complications associated with the underlying high-grade glioma or 
ependymoma disease process, which are unlikely but unknown if related to treatment with 
NovoTTF-200A include the following adverse events: ​
 
●​ Seizure, including Status Epilepticus  
●​ Neurological and functional decline  
●​ Headaches, nausea and/or vomiting  
●​ Death 
 
17.2 UNEXPECTED ADVERSE EVENTS 
 
The following are descriptions of unexpected events, not listed as potential adverse events in 
Section 14.1.  If an event occurs that meets the criteria below, it will be considered a serious 
adverse event for the purposes of the phase I dose escalation scheme detailed in Section 4.1 and 
be reported as described in protocol Section 15.0.  
 
a)  Any grade 4 non-hematological toxicity 
b)  Any grade 3 non-hematological toxicity with the specific exception of  
i. Grade 3 nausea and vomiting of less < 5 days duration responsive to 
antiemetic therapy; 
ii. Grade 3 increased alanine aminotransferase (ALT or SGPT) that return to 
levels that meet initial eligibility criteria within 7 days of treatment interruption 
and that do not recur upon study re-challenge with treatment 
iii. Grade 3 fever or infection < 5 days duration. 
iv. Grade 3 hypokalemia, hypophosphatemia, hypocalcemia and/or 
hypomagnesemia responsive to oral supplementation 
c) Any grade 2 non-hematological toxicity that persists for ≥ 7 
days and is considered sufficiently medically significant or 
sufficiently intolerable by patients that it requires treatment 
interruption. 
d) Grade 2 allergic reactions that necessitate discontinuation of temozolomide or 
bevacizumab will not be considered dose-limiting. 
e) Any Grade 2 or higher adverse event requiring interruption of protocol treatment for > 
7 days or which recurs upon treatment re-challenge. 
 
18.0 ADVERSE EVENT REPORTING ​
 
18.1 DEFINITION OF ADVERSE EVENTS ​
 
As defined by the ICH Guidelines for Good Clinical Practice E2A (CPMP/ICH/377/95), an 
adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
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product, whether or not considered related to this medicinal product. Adverse events include the 
following:  
 
●​ All suspected medication adverse reactions  
●​ All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity.  
●​ Apparently unrelated illnesses, including the worsening of a preexisting illness  
●​ Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident (a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate adverse events.  
●​ Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test).  
●​ Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event. Laboratory abnormalities associated with a clinical event 
(elevated liver enzymes in a patient with jaundice) should be captured in the source 
documents.  
 
Each adverse event is to be classified by the investigator as serious or non-serious. This 
classification of the gravity of the event determines the reporting procedures to be followed. 
 
18.2 GRADING OF AN ADVERSE EVENT  
 
The descriptions and grading scales found in the revised NCI Common Toxicity Criteria 
(CTCAE) version 5.0 will be utilized for assessing severity of adverse events. If the toxicity is 
not characterized adequately by the NCI toxicity scale, the investigator will use the adjectives 
MILD, MODERATE, SEVERE to describe the maximum intensity of the adverse event. For 
purposes of consistency, these intensity grades are defined as follows: 
 
MILD  
Grade 1  
Transient or minimal symptoms, no change in activity 
or need for medication ​
 
MODERATE  
Grade 2  
Symptomatic change, interferes to some extent with 
patient's usual function ​
 
SEVERE  
Grade 3  
Incapacitating, significantly interferes with patient's 
usual function  
 
18.3 DETERMINATION OF CAUSALITY OF ADVERSE EVENTS ​
 
The relationship of the adverse event to the study treatment must be specified using the 
following definitions: 
 
None:  
The event is clearly related to an event that may be due to environmental or 
accidental occurrence or other factors such as the subject’s clinical state, 
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therapeutic interventions, or concomitant drugs administered to the subject. ​
 
Unlikely  
The event is most likely produced by other factors such as the subject’s 
clinical condition, therapeutic interventions, or concomitant drugs 
administered to the subject, and does not follow a known response pattern to 
the study drug or device. ​
 
Possible  
The event follows a reasonable temporal sequence from the time of drug 
administration or use of device, and/or follows a known response pattern to 
the study drug or device, but could have been produced by other factors such 
as the subject's clinical condition, therapeutic interventions, or concomitant 
drugs administered to the subject. ​
 
Probable  
The event follows a reasonable temporal sequence from the time of drug 
administration or use of device, and follows a known response pattern to the 
study drug or device, and cannot be reasonably explained by other factors 
such as the subject's clinical condition, therapeutic interventions, or 
concomitant drugs administered to the subject. ​
 
Definite  
The event follows a reasonable temporal sequence from the time of drug 
administration or use of device, and follows a known response pattern to the 
study drug or device, and cannot be reasonably explained by other factors 
such as the subject's clinical condition, therapeutic interventions, or 
concomitant drugs administered to the subject, and either occurs 
immediately following study drug administration or use of device or 
improves on stopping the study drug or device, or reappears on repeat 
exposure  
​
 
18.4  SERIOUS ADVERSE EVENTS ​
 
When a serious adverse events is identified, treatment with Optune NovoTTF-200A and any 
chemotherapy should be discontinued until resolution of the toxicity.  Treatment with Optune 
NovoTTF-200A should then be restarted, if felt to be clinically appropriate, by the investigator. 
Temozolomide should be restarted at 25% of the previous dose, if felt to be clinically appropriate 
by the investigator. 
 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
serious:  
●​ Death  
●​ Life-threatening (i.e., at immediate risk of death)  
●​ Inpatient hospitalization or prolongation of existing hospitalization  
●​ Persistent or significant disability/incapacity  
●​ Congenital anomaly/birth defect ​
 
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Important adverse events that may not result in death, may not be life-threatening, or do not 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may acutely jeopardize the patient without immediate medical intervention to  
prevent one of the outcomes listed above. Serious may also include any other event that the 
investigator or company judges to be serious. In addition, sites are responsible for reporting 
serious adverse events to their local IRB/EC according to their institutional requirements. Death 
due to disease progression need not be reported to the study monitor. These SAEs will be 
captured in the CRFs as described for regular AEs. ​
 
18.5 ROUTINE ADVERSE EVENT REPORTING ​
 
All adverse events must be reported in the source documentation and CRFs with appropriate 
information, including severity and rating of causality to the study drug/treatment. Adequate 
source documentation must be available to characterize the severity, duration and causality of 
each reported adverse event.  
 
See Section 14.0 Study Monitoring and Data Collection ​
 
18.6 UNANTICIPATED ADVERSE DEVICE EFFECT EVENT (UADE) REPORTING ​
 
Any potential unanticipated adverse device effect (UADE) will be reported to the study monitor 
and local IRB/EC within 10 days of the investigator learning of the event. The medical monitor 
will investigate whether the adverse event is a UADE and, if so, report the UADE to the 
Sponsor, as soon as possible but no later than 3 days after first learning of the event. Expedited 
report for FDA submission and reporting to other IRBs/ECs to follow within 10 working days 
after first learning of the event by the medical monitor. ​
 
The report will contain the following:  
●​ The initials of the subject, patient MRN #, protocol # and title  
●​ The date the event occurred  
●​ A description of the UADE  
●​ An explanation of how the UADE was handled  
●​ A description of the subject's condition  
●​ Indication if the subject remains on the study  
●​ Indication if the event is considered related to the NovoTTF-200A  
●​ Indication if an amendment to the protocol and/or consent form is recommended as a 
result  
 
18.7 ELICITING ADVERSE EVENT INFORMATION  
 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient using concise medical terminology. In addition, each 
trial patient will be questioned about adverse events at each clinic visit following initiation of 
treatment. The question asked will be, “Since your last clinic visit have you had any health 
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problems?” ​
 
18.8 ADVERSE EVENT REPORTING PERIOD  
 
The adverse event reporting period will begin immediately following initiation of treatment with 
the NovoTTF-200A device. Adverse events will be collected through the final study visit. All 
adverse events that occur in trial patients during the adverse event reporting period specified in 
the protocol must be reported on the CRFs, whether or not the event is considered study 
treatment-related. In addition, any known untoward event that occurs beyond the adverse event 
reporting period that the investigator assesses as possibly related to the investigational 
medication/product should also be reported as an adverse event. ​
 
18.9 FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS ​
 
All adverse events should be followed until they are resolved or the investigator assesses them as 
chronic or stable or the patient’s participation in the trial ends. ​
 
In addition, all serious adverse events and those non-serious events assessed by the investigator 
as probably related to the investigational medication/product should continue to be followed 
even after the patient's participation in the trial is over. Such events should be followed until they 
resolve or until the investigator assesses them as “chronic” or “stable.” Resolution of such events 
is to be documented on the appropriate CRF. 
 
19.0 STUDY OUTCOME MEASURES 
 
19.1 SAFETY ANALYSIS 
 
This study’s safety endpoint will be to attempt to assess the safety and tolerability of the Optune 
NovoTTF-200A System when used in combination with temozolomide and bevacizumab for the 
treatment of pediatric high-grade glioma and ependymoma. This safety endpoint will be 
determined using the rules of a standard 3+3 phase I study design and be based on the incidence 
and severity of adverse events and toxicities. Toxicities will be assessed according to the 
“Common toxicity criteria (CTCAE), version 5.0”  
 
19.2 EFFICACY ANALYSIS 
 
There are no primary efficacy endpoints for this study.  However, patients will be followed to 
assess their progression-free and overall survival. While the study is not powered to provide an 
efficacy evaluation, the efficacy date gained from this study may be useful in designing future 
phase II/III investigations. 
 
20.0 STATISTICAL CONSIDERATIONS 
 
The sample size of this study will be determined by the number of severe adverse events related 
to therapy observed.  A minimum of two and a maximum of six patients will be needed to 
complete the phase I portion of the study.  In the event that no severe adverse events related to 
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therapy are observed, the study could be successfully completed with a total of five patients.  The 
anticipated sample size for this study, including the expansion cohort, is a sample size based on 
feasibility and not on any formal power calculations.  
​
21.0 CRITERIA FOR REMOVAL FROM STUDY ​
 
●​ Any serious adverse event deemed life threatening by the treating physician that is 
definitely related to the study device will be cause for immediate cessation of treatment 
for the patient.  
●​ The investigator may remove a patient from the study in case of not complying with 
study protocol.  
●​ Patients will be able to withdraw from the trial at their own request.  
 
22.0 RISK/BENEFIT ANALYSIS ​
 
The risks associated with use of the NovoTTF-200A are principally the risk of electrical or 
mechanical failure leading to electrical shock, electromagnetic interference, etc., as well as the 
risk that the treatment will not be effective in delaying tumor progression or causing regression. 
Additional risks include skin irritation, and skin breakdown or infection at electrode sites. 
Technical failure is extremely unlikely due to stringent compliance with all standard design and 
manufacturing safety protocols. In addition, appropriate measures have been taken to minimize 
the risk to study subjects, including preclinical in vitro and in vivo testing to ensure safe 
operation of the device. ​
​
The most common complication seen in patients is a mild to moderate skin irritation beneath the 
electrode gel. In the pivotal study in recurrent GBM, 116 patients were treated with the 
NovoTTF-200A device without unexpected device events. The phase III trial examining the use 
of the NovoTTF100A in combination with temozolomide demonstrated clear improvement in 
both progression-free and overall survival compared to temozolomide alone. Considering the 
minimal toxicity in both adult and pediatric trials and the promising efficacy seen in several adult 
clinical trials, the small number of patients exposed to this treatment in the current study and the 
and the poor outcome of these patients with other treatments – we conclude that the possible 
benefits of combination treatment with NovoTTF-200A, temozolomide, and bevacizumab 
drastically exceed its potential risks. 
 
23.0 STUDY MONITORING AND QUALITY ASSESSMENT ​
 
An independent medical monitor will be assigned to monitor the safety data from the study. This 
individual should be a qualified physician, other than the Principal Investigator, not associated 
with the protocol, able to provide medical care to research volunteers for conditions that may 
arise during the conduct of the study, and who will monitor the volunteers during the conduct of 
the study.  The medical monitor plays a role in reviewing serious adverse events and 
unanticipated problems. 
 
The medical monitor is required to review all unanticipated problems involving risk to subjects 
or others, serious adverse events and all subject deaths associated with the protocol and provide 
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an unbiased written report of the event.  At a minimum, the medical monitor will provide the 
outcome of the event(s) and in case of a serious adverse event or death, provide the relationship 
of the event to the study device and to participation in the study.  The medical monitor will also  
 
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indicate whether he/she concurs with the details of the report provided by the site principal 
investigator.  Reports of adverse events determined by either the investigator or medical monitor 
to be possibly, probably, or definitely related to study participation and reports of events resulting 
in death will be promptly forwarded to the IRB. All adverse events, regardless of seriousness or 
causality must be reported. See Section 17.0 for reporting guidelines.  
 
The medical monitor and the principal investigator, along with any co-investigators, will monitor 
the study data for safety and integrity.  Monitoring will take place annually.  Interim analysis will 
take place following each enrolled cohort of three patients. 
 
24.0 PROTECTION OF HUMAN SUBJECTS  
 
Privacy ​
 
It is the responsibility of the Research Staff to ensure that protocol patients have received the 
Center’s Notice of Privacy Practices. If the subject has not already done so, personnel of the 
relevant participating Center must try to obtain acknowledgment before the patient participates in 
this study.  
 
The Center’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB/EC and Privacy Board. 
 
25.0 INFORMED CONSENT PROCEDURES ​
 
Research authorization ​
 
Procedures for obtaining Research Authorization: Prior to carrying out any protocol-specific 
procedures, investigators or designated staff will explain fully the details of the protocol, study 
procedures, and the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB/EC Informed Consent, all patients must sign the Research 
Authorization component of the informed consent form. The Research Authorization requires a 
separate signature from the patient. The original signed documents will become part of the 
patient’s medical record, and each patient will receive a copy of the signed documents. All 
patients must provide written informed consent prior to registration and treatment. 
 
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