NovoTTF-200A and Temozolomide Chemoradiation for Newly Diagnosed Glioblastoma

A prospective, single arm, non-randomized, open label pilot trial will enroll ten patients
with histologically-confirmed newly diagnosed GBM who meet all eligibility criteria. Patients
will be recruited to the study by the principal investigator (PI) or one of the
co-investigators (CI) at one institution, Hackensack University Medical Center. Accrual is
expected to continue for 18 months.

The protocol has a planned enrollment of 10 patients. Should patients discontinue treatment
on protocol for reasons unrelated to toxicity (e.g. lost to follow-up, withdrawal of
consent), additional patient (s) may be enrolled to complete enrollment.

Following maximal debulking surgery, patients will undergo a gadolinium enhanced brain MRI
within 72 hours and a screening visit 2 to 4 weeks following surgery. Extent of resection
will be recorded as biopsy, partial resection or gross-total resection based upon residual
enhancing tumor on post-operative MRI.The day prior to XRT start, patients will have a clinic
visit for training and application of the NovoTTF-200A device. During this visit, the patient
will be educated regarding general use and maintenance of the device, with a particular focus
upon strategies to prevent, identify and manage dermatologic adverse events (dAE).
Temozolomide will be dosed nightly during XRT as per standard of care, and NovoTTF-200A will
be worn continuously, removed during XRT and replaced as soon as possible thereafter.

During XRT and for 12 weeks to follow, the patient will have study visits at regular
intervals (TAB A) for a physical examination and to assess toxicity and device compliance.
Visits outlined in TAB A are in addition to weekly visits during radiotherapy with the
treating radiation oncologist. MRI will be obtained at 4 weeks (+/-7 days) and 12 weeks (+/-7
days) following completion of XRT, and maintenance temozolomide will recommence in 5/28 day
cycles as per standard of care. Objective response will be assessed as defined by the
Response Assessment in Neuro-Oncology (RANO) criteria (TAB C) by the treating physician and
confirmed by a second investigator.

In the case of suspected pseudoprogression, continued treatment and subsequent evaluations
will help clarify whether it is true progression. Patients may continue treatment at the
discretion of the investigator. If subsequent evaluations suggest that the tumor has in fact
progressed, the date of progression will reflex to the date when the issue was first raised.
However, if subsequent evaluations demonstrate improvement without change in therapy, the
initial tumor increase may be considered pseudoprogression and response may be recorded as
not evaluable for that time point. In the case of clinical progression, an unscheduled MRI
will be obtained within 1 week of the investigator becoming aware of the clinical
progression. No additional MRIs will be required after progression.

Temozolomide and NovoTTF-200A will continue until the final study visit, or until disease
progression or unacceptable toxicity. Thereafter, temozolomide, MRI and response assessments
will continue as per standard of care. Following the final study visit, the patient will be
followed at a minimum of every two months for survival, either by phone or in person. If the
patient is free of unacceptable toxicity attributable to NovoTTF-200A, they will be offered
the opportunity to continue the device at no financial cost, but without obligation to do so.

Unacceptable toxicity includes the occurrence of device related serious adverse events or
clinical and functional deterioration considered by the investigator to be prohibitive of
continuing treatment. Treatment with the NovoTTF-200A device does not need to be terminated
in the case of temozolomide toxicity.

The primary endpoint will be safety and tolerability of combined modality treatment with
radiotherapy, temozolomide and NovoTTF-200A, based upon the incidence and severity of adverse
events. Secondary endpoints will be overall survival, progression free survival and quality
of life.

Inclusion Criteria:

1. Histologically confirmed GBM using WHO criteria.

2. Age ≥ 18 years

3. Maximal debulking surgery (at the discretion of the investigator). Biopsy alone is not
exclusionary.

4. KPS ≥ 70

5. Life expectancy of at least 3 months.

6. Sexually active participants must agree to the strict use of barrier contraception.

7. Patients must be able to understand the investigational nature of the study and
provide informed consent.

8. Adequate hematologic function:

1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

2. Platelet count ) ≥ 100 x 109/L

3. Hemoglobin ≥ 10 g /dL

9. Adequate liver function

1. Total bilirubin ≤ 1.5 x ULN

2. AST and ALT ≤ 2.5 x ULN

10. Adequate renal function

a. Creatinine ≤ 1.25 x ULN

11. International normalized ratio (INR) or PT and activated partial thromboplastin time
(aPTT): 1.5 x ULN (except for subjects receiving anticoagulation therapy). Use of
anticoagulants is permitted as long as the INR or aPTT are within therapeutic limits
(according to the medical standard of the institution).

Exclusion Criteria:

1. Active participation in another clinical treatment trial. Concomitant protocols for
data or tissue collection without intervention are permitted.

2. Any prior treatment for GBM aside from surgery, including carmustine wafers.

3. Women who are pregnant or nursing.

4. Severe acute or chronic medical or psychiatric condition or laboratory abnormality
that could increase the risk associated with trial participation, NovoTTF-200A device
use or interfere with interpretation of trial results and, in the judgment of the
investigator, would make the patient inappropriate for entry into the trial. This
includes but not limited to:

1. Patients with inadequately healed surgical incisions or other dermatologic scalp
toxicity at baseline (grade 2 or higher, as defined in Section VIII) upon which
transducer leads may require placement.

2. Known HIV or other immunosuppressive disease, chronic hepatitis B or hepatitis C

3. Dementia or significantly altered mental status that would prohibit the
understanding or rendering of informed consent and compliance with the
requirements of the protocol.

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

6. Infratentorial glioblastoma.

7. Past hypersensitivity reaction to temozolomide or DTIC.

8. Psychiatric illness that compromises the informed consent process, at the discretion
of the investigator.

9. Inability or unwillingness to return for required visits.

10. Previous cytotoxic therapy within the last 5 years.

11. Inability to begin temozolomide concomitant to radiation therapy, for reasons 4 or 7
above.