HUMC 1612: Optune NovoTTF-200A System

This phase I trial will utilize a standard 3+3 design to determine the safety and
tolerability of the Optune NovoTTF-200A System in pediatric high-grade glioma patients. The
initial cohort of patients will receive treatment with the Optune NovoTTF-200A System alone
and will consist of children with recurrent high-grade gliomas. Newly-diagnosed patients will
be excluded from this initial cohort as withholding more proven initial therapies may be
considered unethical.

Patients enrolled to the Optune NovoTTF-200A System monotherapy cohort will receive treatment
with 200kHz for a minimum of 18 hours per day in 28 day cycles. 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.

If the Optune NovoTTF-200A System is found to be well-tolerated in pediatric patients with
recurrent high-grade gliomas, then the study will proceed to determine the safety and
tolerability of the device when used in combination with chemotherapy agents, temozolomide
and bevacizumab.This second cohort of patients will include children with both newly
diagnosed and recurrent high-grade gliomas. Children with recurrent tumors will only be
eligible if they have not previously received therapy with temozolomide and/or bevacizumab.
(The lone exception to this rule is temozolomide and/or bevacizumab administered solely
during radiation therapy.) Patients enrolled to the Optune NovoTTF-200A System plus
temozolomide and bevacizumab cohort will receive TTField treatment with 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.

Once a patient is assigned to a treatment cohort, 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 until any criterion for discontinuation (clinical or radiological
progression of disease, clinically unacceptable toxicity, completion of treatment, etc.) is
met.

Inclusion Criteria:

- Patients must have a minimum head circumference of 44 cm

- Patients must have a histologically- or cytologically-confirmed supratentorial
high-grade glioma (either WHO Grade III anaplastic astrocytoma or WHO Grade IV
glioblastoma multiforme). Patients in the initial cohort must have a tumor that is
progressive or recurrent to standard chemotherapy. Patients in the second cohort may
be newly diagnosed or have a tumor that is progressive, recurrent, or refractory to
standard chemotherapy.

- 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.

- Patients must be enrolled before treatment begins. Treatment must start within 14 days
of study enrollment.

- All clinical and laboratory studies to determine eligibility must be performed within
7 days prior to enrollment unless otherwise indicated in the eligibility section.

- Recurrent high-grade glioma patients must begin therapy within four weeks of
documented tumor progression by MRI scan. 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.

- 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.

- Able to undergo adequate tumor imaging, via magnetic resonance imaging (MRI) scan to
evaluate disease evolution.

- Adequate hematologic, renal, liver function as demonstrated by laboratory values: ANC
≥ 1,000/ul Hemoglobin ≥8.0 gm/dl Platelet count ≥ 100,000/ul

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. 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

- Negative pregnancy test in women of childbearing potential within 7 days of initiating
investigational therapy

- Recent mothers must agree not to breast feed while receiving medications on study

- Patient or legal guardian must give written, informed consent or assent (when
applicable).

Additional Inclusion criteria for Cohort 2 (Optune NovoTTF-200A + chemotherapy) only:

- Able to swallow and ingest oral medication or have a NG or G-tube for drug
administration

- 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.

Exclusion Criteria:

- Head circumference < 44 cm

- Infra-tentorial tumor

- Use of any other investigational drug within five half-lives of that drug prior to the
initiation of protocol therapy

- 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)

- Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE
version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could
impact on safety outcome assessment

- Any surgery within 14 days prior to initiation of protocol therapy (excluding shunt or
line insertion)

- Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other
implanted electronic devices in the brain, or documented clinically significant
arrhythmias.

- Evidence of increased intracranial pressure (midline shift > 5mm, clinically
significant papilledema, vomiting and nausea or reduced level of consciousness)

- Known > Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan
within the last 1 month. Patients with resolving hemorrhage changes, punctuate
hemorrhage or hemosiderin may enter the study

- Pregnant female patients, Pregnancy tests with a negative result must be obtained in
all post-menarchal females.

- Lactating females must agree they will not breastfeed a child while on this study.

- 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.

- 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

Additional Exclusion criteria for Cohort 2 (Optune NovoTTF-200A + chemotherapy) only:

- Prior therapy with temozolomide and/or bevacizumab. The lone exception to this rule is
temozolomide and/or bevacizumab administered solely during radiation therapy.

- Known hypersensitivity to temozolomide or bevacizumab

- Patients who are unable to take oral medications because of significant uncontrolled
vomiting

- Patients with 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

- Patients with known clinically significant bleeding diathesis or coagulopathy

- Patients who have experienced arterial thromboembolic events, including transient
ischemic attacks or cerebrovascular accidents

- Patients previously diagnosed with deep venous thrombosis (including pulmonary
embolism), and 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).

- History of an abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within the last 6 months prior to study entry.

- Patients with a serious or non-healing wound, ulcer, or bone fracture.

- History of allergic reaction to Chinese hamster ovary cell products, or other
recombinant human antibodies