Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM)

PAST CLINICAL EXPERIENCE:

The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has
been tested in a large prospective, randomized trial, in recurrent GBM. The outcome of
subjects treated with the NovoTTF-100A device was compared to those treated with an
effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A subjects
had comparable overall survival to subjects receiving the best available chemotherapy in the
US today. Similar results showing comparability of NovoTTF-100A to BSC chemotherapy were
seen in all secondary endpoints.

Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer
side effects in general, significantly fewer treatment related side effects, and
significantly lower gastrointestinal, hematological and infectious adverse events compared
to controls. The only device-related adverse events seen were a mild to moderate skin
irritation beneath the device electrodes. 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.

In a small scale pilot trial in newly diagnosed GBM patients, the treatment was well
tolerated and suggested that NovoTTF-100A may improve time to disease progression and
overall survival of newly diagnosed GBM patients. Although the number of patients in the
pilot trial was small, The FDA has determined that the data gathered so far warrant testing
of NovoTTF-100A treatment as a possible therapy for patients with newly diagnosed GBM.

DESCRIPTION OF THE TRIAL:

All patients included in this trial are newly diagnosed GBM patients who underwent a biopsy
or surgery (with or without Gliadel wafers), followed by radiation therapy in combination
with Temozolomide chemotherapy. In addition, all patients must meet all eligibility
criteria.

Eligible patients will be randomly assigned to one of two groups:

1. Treatment with the NovoTTF-100A device in combination with Temozolomide chemotherapy.

2. Treatment with Temozolomide alone, as the best known standard of care.

Patients will be randomized at a 2:1 ratio (2 of every three patients who participate in the
trial will be treated with the NovoTTF-100A device). Baseline tests will be performed in
patients enrolled in both arms, including specific genetic tests done using tumor samples
obtained during their initial surgery. If assigned to the NovoTTF-100A in combination with
Temozolomide group, the patients will be treated continuously with the device until second
progression. They will also receive temozolomide and possibly a second line treatment that
can be one of the following: re-operation, local radiotherapy (gamma-knife), a second line
of chemotherapy or a combination of the above.

NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays
on the head. Electrode array placement will require shaving of the scalp before and
frequently during the treatment. After an initial short visit to the clinic for training and
monitoring, patients will be released to continue treatment at home where they can maintain
their regular daily routine.

During the trial, regardless of which treatment group the patient was assigned to, he or she
will need to return once every month to the clinic where an examination by a physician and a
routine laboratory examinations will be done. These routine visits will continue for as long
as the patient's disease is not progressing for the second time under the study treatment.
If such occurs, patients will need to return once per month for two more months to the
clinic for similar follow up examinations.

During the visits to the clinic patients will be examined physically and neurologically.
Additionally, routine blood tests will be performed. A routine MRI of the head will be
performed at baseline and every second month thereafter, until second progression. After
this follow up plan, patients will be contacted once per month by telephone to answer basic
questions about their health status.

SCIENTIFIC BACKGROUND:

Electric fields exert forces on electric charges similar to the way a magnet exerts forces
on metallic particles within a magnetic field. These forces cause movement and rotation of
electrically charged biological building blocks, much like the alignment of metallic
particles seen along the lines of force radiating outwards from a magnet.

Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
TTFields are alternating electric fields of low intensity. This means that they change their
direction repetitively many times a second. Since they change direction very rapidly (200
thousand times a second), they do not cause muscles to twitch, nor do they have any effects
on other electrically activated tissues in the body (brain, nerves and heart). Since the
intensities of TTFields in the body are very low, they do not cause heating.

The breakthrough finding made by NovoCure was that finely tuned alternating fields of very
low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
multiplying, TTFields cause the building blocks of these cells to move and pile up in such a
way that the cells physically explode. In addition, cancer cells also contain miniature
building blocks which act as tiny motors in moving essential parts of the cells from place
to place. TTFields cause these tiny motors to fall apart since they have a special type of
electric charge.

As a result of these two effects, cancer tumor growth is slowed and can even reverse after
continuous exposure to TTFields.

Other cells in the body (normal healthy tissues) are affected much less than cancer cells
since they multiply at a much slower rate if at all. In addition TTFields can be directed to
a certain part of the body, leaving sensitive areas out of their reach.

In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very
few side effects and promising affectivity in slowing or reversing this disease.

Inclusion Criteria:

1. Pathological evidence of GBM using WHO classification criteria.

2. > 18 years of age.

3. Received maximal debulking surgery and radiotherapy concomitant with Temozolomide
(45-70Gy):

1. Patients may enroll in the study if received Gliadel wafers before entering the
trial

2. Any additional treatments received prior to enrollment will be considered an
exclusion.

3. Minimal dose for concomitant radiotherapy is 45 Gy

4. Karnofsky scale ≥ 70

5. Life expectancy at least 3 months

6. Participants of childbearing age must use effective contraception.

7. All patients must sign written informed consent.

8. Treatment start date at least 4 weeks out from surgery.

9. Treatment start date at least 4 weeks out but not more than 7 weeks from the later of
last dose of concomitant Temozolomide or radiotherapy.

Exclusion Criteria:

1. Progressive disease (according to MacDonald Criteria). If pseudoprogression is
suspected, additional imaging studies must be performed to rule out true progression.

2. Actively participating in another clinical treatment trial

3. Pregnant

4. Significant co-morbidities at baseline which would prevent maintenance Temozolomide
treatment:

1. Thrombocytopenia (platelet count < 100 x 103/μL)

2. Neutropenia (absolute neutrophil count < 1.5 x 103/μL)

3. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)

4. Significant liver function impairment - AST or ALT > 3 times the upper limit of
normal

5. Total bilirubin > upper limit of normal

6. Significant renal impairment (serum creatinine > 1.7 mg/dL)

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

6. Infra-tentorial tumor

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

8. History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity
to DTIC.