A Phase II Study of NovoTTF-200A Alone and With Temozolomide in Patients With Low-Grade Gliomas

Approximately 2,000 to 3,000 low-grade gliomas (LGGs) are diagnosed in adults each year in
the United States. Based on a variety of prognostic factors the median overall survival
ranges from 3 to 9 years.

NovoTTF-200A is a device that produces alternating electrical fields within the human body
that disrupt cell division. These very low intensity intermediate frequency electric fields
(TTFields) impair the growth of tumor cells through the arrest of cell division and inducing
apoptosis.

Although FDA approved for the treatment of recurrent or progressive glioblastoma, further
investigation of NovoTTF-200A is warranted, in the setting of low-grade glioma where it has
the potential to stunt tumor growth without significant toxicity. NovoTTF-200A has also been
shown to be safe combined with adjuvant 5-day temozolomide regimen in newly diagnosed
glioblastoma in an ongoing clinical trial. Given the low proliferative index in low-grade
gliomas, combining NovoTTF-200A with metronomic chemotherapy may be more effective.

This is a phase II randomized, 2-arm, open label study of NovoTTF-200A alone or combined with
daily temozolomide for the treatment of patients with newly diagnosed low-grade gliomas.

Patients will be randomized 1:1 to one of two arms for a total of 42 patients (21 per arm).
Arm A will receive NovoTTF-200A only and Arm B will receive NovoTTF-200A and low-dose (50
mg/m2) daily temozolomide regimen.

All patients providing informed consent will be screened for eligibility. Baseline
assessments will include vital signs, physical exam, blood hematology and chemistries,
Karnofsky Performance Status (KPS) evaluation, Quality of Life (QOL) assessment using the
Functional Assessment of Cancer Therapy-Brain (FACT-Br), a neurological exam and
neuro-imaging (MRI) of brain. An extra blood sample will be collected for biomarker studies.

Clinical evaluations include physical exam, vitals, KPS, neurological exam and blood
hematology and chemistries (obtained once every month throughout treatment). Neuro-imaging
and assessment for response will be performed approximately every 3 months. QOL will be
assessed with the KPS rating scale and the FACT-Br questionnaire at screening and then every
six months during treatment. Blood will be collected for correlative studies on Day 1 of
every even cycle. Any molecular information derived from the correlative studies or clinical
care will be associated with the patient's response.

Patients will continue monthly cycles of treatment for 12 cycles or until disease progression
or unacceptable toxicity (whichever occurs first). For those in Arm B, patients may continue
NovoTTF-200A treatment if temozolomide is discontinued early for toxicity. An end of
treatment visit for clinical evaluations and safety assessments will be performed
approximately four to six weeks of withdrawing from study treatment. Patients discontinuing
study treatment will be followed at months 18 and 24 with tumor assessments if they
discontinued from study treatment without disease progression and for survival.

Inclusion Criteria:

- Histologically confirmed low-grade glioma including astrocytoma grade 2,
oligodendroglioma grade 2, or oligoastrocytoma grade 2.

- Tumor is supratentorially located and measureable.

- Disease that has not received prior radiation, radiosurgery, chemotherapy, or other
investigational treatment directed at the brain tumor at any time. Previous surgical
procedures is allowed.

- Age ≥ 18 years.

- Life expectancy > 12 weeks.

- Either not receiving steroids for disease symptoms or are on stable dose of steroids
for at least 5 days.

- Karnofsky Performance Status (KPS) ≥ 60%

- Adequate hematologic function evidenced by:

- Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L

- Hemoglobin ≥ 9.0 g/dL

- Adequate renal function evidenced by:

- AST/SGOT and ALT/SPGT ≤ 2.5 X institutional upper limit of normal

- Total bilirubin ≤ 1.5 x institution's ULN

- Serum creatinine ≤ 1.5 x institution's ULN

Exclusion Criteria:

- Pilocytic astrocytoma, ganglioglioma, pleomorphic xanthastrocytoma, or
dysembryoplastic neuroepithelial tumors are not eligible.

- Current or anticipated use of other investigational agents.

- Implanted electronic medical device in the brain (e.g., deep brain stimulator, vagus
nerve stimulator, programmable shunt).

- Patients who are less than 4 weeks from surgery or have insufficient recovery from
surgical-related trauma or wound healing.

- Severe or uncontrolled medical disorder that would, in the investigator's opinion,
impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal
disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric
illness/social situations that would limit compliance with study requirements).

- Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable
cardiac or coronary artery disease.

- Pregnant or nursing.