NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma

This will be an open label Phase II trial in adults with recurrent glioblastoma (GBM). The
NovoTTF-100A treatment and Bevacizumab will be administered on an outpatient basis;
NovoTTF-100A treatment will be initiated in the outpatient clinic.

PRIMARY OBJECTIVES:

I. To determine the efficacy of the combination of bevacizumab and NovoTTF-100A in
bevacizumab-naive patients with recurrent glioblastoma (GBM) as measured by 6-month
progression-free survival (PFS6).

SECONDARY OBJECTIVES:

I. To assess safety and tolerability of the combination of bevacizumab and Novo-TTF-100A in
this patient population.

II. To evaluate overall survival in this population. III. To determine objective response
rate (ORR) by modified Revised Assessment in Neuro-Oncology (RANO) criteria in this
population.

IV. To assess time-to-progression in this population. V. To assess neurocognitive function
(NCF) and quality of life (QOL) in this population.

OUTLINE:

Patients receive bevacizumab intravenously (IV) on days 1 and 15. Patients also undergo
electric field therapy with NovoTTF-100A for at least 18 hours daily. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 28 days.

Inclusion Criteria:

- Patients with histologically confirmed glioblastoma or other grade IV malignant glioma
(i.e. gliosarcoma, small cell glioblastoma, etc.), recurrent after prior external-beam
fractionated radiotherapy and temozolomide chemotherapy.

- Patients with up to two prior recurrences are allowed.

- Karnofsky performance status ≥70.

- Patients must have the following laboratory values:

- Absolute neutrophil count (ANC) ≥1.5 x 10^9/L

- Platelets ≥ 100 x 10^9/L

- Hemoglobin (Hgb) > 9 g/dL

- Serum total bilirubin: ≤ 1.5 x ULN

- ALT and AST ≤ 3.0 x ULN

- Serum creatinine ≤ 1.5 x ULN

- Blood coagulation parameters: INR ≤ 1.5

- Minimum interval since completion of radiation treatment is 12 weeks

- Minimum interval since last drug therapy:

- 3 weeks since last non-cytotoxic therapy

- 3 weeks must have elapsed since the completion of a non-nitrosourea-containing
chemotherapy regimen

- 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen.

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information.

- Patients with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception. The effects of
bevacizumab on developing fetus or nursing infant are not known. Female patients of
child-bearing potential must have a negative pregnancy test.

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast,
adequately treated stage I or II cancer from which the patient is in complete
remission. Patients with other prior malignancies must be disease-free for ≥ three
years.

- Patients must be maintained on a stable corticosteroid regimen from the time of their
baseline scan until the start of treatment and/or for at least 5 days before starting
treatment.

Exclusion Criteria:

- Patients who have had previous treatment with bevacizumab, and or NovoTTF 100A system.

- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting
study drug, or patients who have had minor procedures, percutaneous biopsies or
placement of vascular access device ≤1 week prior to starting study drug, or who have
not recovered from side effects of such procedure or injury

- Patients with impaired cardiac function or clinically significant cardiac diseases,
including any of the following:

- History or presence of serious uncontrolled ventricular arrhythmias

- Any of the following within 6 months prior to starting study drug: myocardial
infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG),
Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient
Ischemic Attack (TIA), Pulmonary Embolism (PE)

- Uncontrolled hypertension (defined by a systolic blood pressure (SBP) ≥ 160 mm Hg
or diastolic blood pressure (DBP) ≥ 100 mm Hg while on anti-hypertensive
medications)

- Patients with cirrhosis, or active viral or nonviral hepatitis.

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

- Infra-tentorial tumor

- Evidence of increased intracranial pressure (clinically significant papilledema,
vomiting and nausea or reduced level of consciousness)

- Known sensitivity to conductive hydrogels

- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory)

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable
safety risks or compromise compliance with the protocol

- Pregnant or breast-feeding women

- Patients unwilling or unable to comply with the protocol

- Patients with leptomeningeal disease