Feasibility Trial of Optune for Children With Recurrent or Progressive Supratentorial High-Grade Glioma and Ependymoma

Primary Objectives:

I To establish the feasibility of treatment with the Optune device in pediatric patients with
recurrent/refractory/progressive supratentorial malignant glioma and ependymoma.

II To describe the Optune device treatment-related toxicities in children with
recurrent/refractory/progressive supratentorial malignant glioma and ependymoma.

Secondary Objectives:

I To estimate the response rate and Event-Free Survival (EFS) as markers of anti-tumor
activity of the Optune device within the context of a feasibility trial.

II To assess the association of anti-tumor activity with compliance in Optune device use
within the context of a small feasibility study.

III To explore the impact of the Optune device on the children and families undergoing this
therapy, and to explore the association between demographic (e.g., SES, gender), disease
(e.g., risk status), treatment, and behavioral variables with health-related quality of life
(QoL) changes.

IV To explore the association of apparent diffusion coefficient (ADC) values within the tumor
and correlate with response to Optune treatment and EFS.

Outline:

The Optune will be worn for a minimum of 18 hours a day, with a recommendation of 22
hours/day for at least 23 days in a 28-day cycle. Cycle 1 includes 7 days training period,
followed by 28 days treatment (total 35 days). The patients will receive multiple 28-day
cycles of continuous Optune treatment. In the absence of treatment related serious adverse
events or disease progression, Optune will continue up to 26 cycles.

The patients will be followed up for 30 days after the last application of the Optune device.

Inclusion Criteria:

- Diagnosis: Patients must have a histologically confirmed diagnosis of supratentorial
high-grade glioma or supratentorial ependymoma that is recurrent, progressive or
refractory.

- Patients must have failed standard therapy and at the time of study entry have
recurrent, progressive or refractory disease with no known curative options.

- Disease Status: Patients must have bi-dimensionally measureable disease, defined as at
least one lesion that can be accurately measured in at least two planes

- This disease must be located primarily in the supratentorial region

- Patients with significant disease that is metastatic outside of the
supratentorial region are ineligible

- Age: Patients must be ≥ 5 but ≤ 21 years of age at the time of enrollment.

- Prior Therapy: Patients must have recovered from the acute treatment related
toxicities (defined as ≤ grade 1) of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study.

- Myelosuppressive Chemotherapy: Patients must have received last dose of known
myelosuppressive chemotherapy >21 days prior to enrollment; >42 days if nitrosurea.

- Biologic Agent: Biologic agent must have recovered from any acute toxicity potentially
related to the agent and received their last dose of the biologic agent > 7 days prior
to study enrollment.

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur.

- Immunomodulatory treatment: Patient must have received the last dose >21 days prior to
enrollment.

- Monoclonal antibody treatment and agents with known prolonged half-lives: At least
three half-lives must have elapsed prior to enrollment.

- Radiation: Patients must have had their last fraction of:

- Craniospinal irradiation (>24Gy) > 3 months prior to enrollment

- Focal irradiation > 42 days prior to enrollment

- Local palliative irradiation (small port) > 14 days

- Surgery: Optune device application start date must be at least 4 weeks (28 days) from
CNS surgical procedure. Excluding VP shunts, Endoscopic Third Ventriculostomy (ETV)
for which treatment could start 10 days post procedure. Non-CNS surgical procedures
such as but not limited to central venous catheter insertion at the discretion of
treating physician and study chair.

- Inclusion of Women and Minorities: Both males and females of all races and ethnic
groups are eligible for this study.

- Neurologic Status: Patients with neurological deficits should be stable for a minimum
of 1 week prior to enrollment.

- Performance Status: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky
Performance Score (LPS for ≤ 16 years of age) assessed within two weeks of enrollment
must be ≥ 60. Patients who are unable to walk because of neurologic deficits, but who
are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score.

- Organ Function: Patients must have organ and marrow function as defined below:

Absolute neutrophil count ≥ 1.0 X 109/L; Platelets ≥ 100 X 109/L (transfusion independent);
Hemoglobin ≥8g/dl (may receive transfusions); Total bilirubin ≤1.5 times institutional
upper limit of normal (ULN); ALT(SGPT) ≤3 times institutional upper limit of normal;
AST(SGOT) ≤3 times institutional upper limit of normal; Albumin ≥2 g/dl. Serum creatinine
based on age/gender as noted below. Patients that do not meet the criteria below but have a
24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are
eligible.

Age Maximum Serum Creatinine (mg/dL)

3 to < 6 years 0.8 (Male) 0.8 (Female); 6 to < 10 years 1 (Male) 1 (Female); 10 to < 13
years 1.2 (Male) 1.2 (Female); 13 to < 16 years 1.5 (Male) 1.4 (Female);

≥ 16 years 1.7 (Male) 1.4 (Female).

- Head circumference: Patients must have minimum head circumference of 44 cm.

- Compliance in Optune Device Usage: Patients must be willing to use the Optune device
≥18 hours/day for at least 23 days in a 28-day cycle, and keep head shaved throughout
treatment.

- Pregnancy Status: Female patients of childbearing potential must have a negative serum
or urine pregnancy test.

- Pregnancy Prevention: Patients of childbearing or child fathering potential must be
willing to use a medically acceptable form of birth control, which includes
abstinence, while being treated on this study.

- Informed Consent: The patient or parent/guardian is able to understand the consent and
is willing to sign a written informed consent document according to institutional
guidelines.

- Steroids: If patient is on corticosteroids, the dose must be stable or decreasing for
at least 5 days prior to enrollment.

Exclusion Criteria:

- Systemic Illness: Patients with any clinically significant unrelated systemic illness
(serious infections or significant cardiac, pulmonary, hepatic or other organ
dysfunction), that in the opinion of the investigator would compromise the patient's
ability to tolerate protocol therapy, put them at additional risk for toxicity or
would interfere with the study procedures or results.

- Other Malignancy: Patients with a history of any other malignancy.

- Concurrent Therapy: Patients who are receiving any other anticancer or investigational
drug therapy are not eligible.

- Inability to Participate: Patients who in the opinion of the investigator are
unwilling or unable to return for required follow-up visits or obtain follow-up
studies required to assess toxicity to therapy or to adhere to device usage plan,
other study procedures, and study restrictions.

- Tumor Location: Patients with primarily infra-tentorial or spinal cord tumor are not
eligible.

- Tumor Dissemination: Patients for who clinical suspicion is present of metastatic
disease in the CSF or Spine must have MRI of Spine and CSF obtained (Lumbar puncture
or through ommaya, EVD or Shunt) with negative cytology. Patients with CSF that is
positive for tumor cells or metastatic disease found on MRI are ineligible.

- Skull Defects: Patients with major skull defects (such as missing bone without
replacement) are not eligible.

- Neurological Disorder: Patients with active implanted electronic devices in the brain
or spinal cord such as programmable VP shunts, deep brain stimulators, vagus nerve
stimulators, are not allowed.

- Cardiac Disorder: Patients with pacemaker, defibrillator, or documented significant
arrhythmia, are not allowed.

- Intracranial Objects: Patients with foreign body intracranially, such as bullet
fragments, are not allowed, with the exception of VP-shunts (non-programmable) and
Ommaya catheters.

- Allergy: Patients with history of hypersensitivity to conductive hydrogel are not
eligible.