Open-Label Pilot Study of OPTUNE® With High Density Transducer Arrays for the Treatment of Recurrent GBM

EF-33: An Open-Label Pilot Study of OPTUNE® (TTFields, 200 Khz) With High Density Transducer Arrays for the Treatment of Recurrent Glioblastoma

This is a prospective, open-label, single arm, historical control pilot study aimed to test the effectiveness and safety of TTFields delivered through high intensity arrays in recurrent glioblastoma.

The Optune® System is an investigational , portable, battery operated medical device in this study delivering 200 kHz TTFields to the brain using high intensity transducer arrays for the treatment of patients at the age of 18 years or older with first or second recurrence of Glioblastoma Multiforme (GBM)

Optune® is a medical device that has been approved for the treatment of recurrent and newly diagnosed glioblastoma (GBM) by the Food and Drug Administration (FDA) in the United States. Optune® has obtained a CE mark in Europe for recurrent and newly diagnosed GBM.

TTFields intensity has been shown to be positively correlated with patient outcome. The new transducer array design is expected to reduce skin heating and thus enable delivery of higher TTFields intensities while keeping the safety profile of the treatment unchanged.

The purpose of the study is to test if delivering TTFields using high intensity transducer arrays for recurrent GBM significantly improves the clinical outcome of patients, compared to using the standard transducer arrays.

The study will enroll 25 patients.

All patients included in this clinical investigation are patients with histologically confirmed diagnosis of GBM with first or second radiological disease progression per RANO criteria.

In addition, all patients must meet all eligibility criteria.

Baseline assessments will be performed to confirm patient eligibility in the study.

Enrolled patients will be treated continuously with the device until disease progression per RANO criteria or 18 months (the earlier of the two) unless any of the treatment discontinuation conditions described under criteria for patient withdrawal or termination are met.

Concurrent brain directed antitumor therapy or procedures beyond TTFields is prohibited.

TTFields treatment will start within 28 days following signing the informed consent.

After the initial visit, subjects will continue treatment at home, while pursuing normal daily routines. Subjects are required to use the device for at least 18 hours a day. Short breaks in treatment for personal hygiene and other personal needs is allowed. Total usage time will be recorded and provided to the sponsor.

Subjects will be required to return to the clinic every 4 weeks and every 8 weeks after first 12 visits, until disease progression. At each study visit an examination by a physician and a routine laboratory examination will be performed.

A contrast enhanced MRI of the head will be performed at baseline and every 4 weeks for the first 24 weeks and then at least every 12 weeks, until disease progression.

A post-treatment termination visit will be performed approximately 30 days after discontinuation of TTfields treatment or disease progression (the latter of the two).

Following disease progression, subjects will be contacted once per month by telephone to answer basic questions about their health status.

Pathological analysis of GBM tumor samples, which may be obtained prior and during the study period, will be performed based on subjects' consent to have an experimental pathological examination of their tumors.

Inclusion Criteria:

1. Histologically confirmed diagnosis of GBM according to WHO classification criteria.
2. Age ≥ 18 years
3. Not a candidate for further radiotherapy or additional resection of residual tumor.
4. Patients with first or second radiological disease progression per RANO criteria documented by MRI within 4 weeks prior to starting therapy with the following restriction: disease progression must be either growth of the enhancing lesion or a new lesion.
5. Karnofsky performance status ≥ 70
6. Life expectancy ≥ least 3 months
7. Participants of childbearing age must use highly effective contraception. An effective method of birth control is defined as one that results in a failure rate of less than 1% per year when used consistently and correctly. The Investigator must approve the selected method, and may consult with a gynecologist as needed.
8. All patients must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
9. Treatment start date at least 4 weeks out from brain surgery chemotherapy or irradiation therapy.

Exclusion Criteria:

1. Infratentorial or leptomeningeal disease

2. Treatment with Optune® (for newly diagnosed or recurrent disease) prior to enrollment.

3. Participation in another clinical treatment study during screening and treatment phase of the study.

4. Pregnancy or breast-feeding.

5. Significant co-morbidities at baseline, as determined by the investigator:

   1. Thrombocytopenia (platelet count < 100 x 103/μL)
   2. Neutropenia (absolute neutrophil count < 1 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 > 1.5 x upper limit of normal
   6. Significant renal impairment (serum creatinine > 1.7 mg/dL, or > 150 µmol/l)
   7. History of any psychiatric condition that might impair patient's ability to understand or comply with the requirements of the study or to provide consent

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

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

8. Admitted to an institution by administrative or court order.

9. Known allergies to medical adhesives or hydrogel

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