Pivotal, Randomized, Open-label Study of Optune® (Tumor Treating Fields) Concomitant With RT & TMZ for the Treatment of Newly Diagnosed GBM

Study Overview
=================
Brief Summary
-----------------
To test the effectiveness and safety of Optune® given concomitantly with radiation therapy (RT) and temozolomide (TMZ) in newly diagnosed GBM patients, compared to radiation therapy and temozolomide alone. In both arms, Optune® and maintenance temozolomide are continued following radiation therapy.

Detailed Description
-----------------
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. The current standard of care for GBM includes the addition of Optune® to maintenance temozolomide (TMZ), following the completion of radiation therapy (RT). The purpose of the current study is to test if the earlier introduction of Optune®, at the time of radiation therapy (which is given together with temozolomide), improves clinical outcomes compared to the standard of care. The study will randomize 950 subjects equally to one of two treatment arms: Treatment arm I: Patients receive TTFields at 200 kHz to the brain using the Optune® System together with RT and TMZ, followed by maintenance TMZ concomitant with the Optune® treatment. Treatment arm II: Patients receive RT and TMZ alone, followed by maintenance TMZ concomitant with TTFields at 200 kHz to the brain using the Optune®. All patients are to receive standard RT and TMZ treatment followed by maintenance TMZ chemotherapy and Optune® according to the current standard of care regimen. Optune® will continue until second disease progression per RANO Criteria or 24 months (the earlier of the two) unless any of the treatment discontinuation conditions described under criteria for patient withdrawal or termination are met. After surgery or biopsy, subjects that would like to participate will be required to submit samples of their tumor to a lab for testing. The results of this test will be used for randomization into the trial. If the subject is assigned to the treatment group that will start Optune® therapy during radiation therapy, Optune® therapy will begin within 7 days of enrolling in the study and no later than the first day of RT and TMZ treatment. 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 until study participation ends. Once every 8 weeks until the tumor potentially returns twice, subjects will have a contrast MRI of the head and neurological exam performed for the first 6 months of the study and then at least every three months until a total time period of 24 months.Once every 12 weeks until second disease progression, subjects will also fill out a quality of life questionnaire. After the second time the tumor returns, subjects will return to the clinic for one final visit approximately 30 days after the last treatment with Optune®. After discontinuing Optune® subjects will be contacted once per month by telephone to answer basic questions about their health status.

Official Title
-----------------
EF-32: Pivotal, Randomized, Open-Label Study of Optune® (Tumor Treating Fields, 200kHz) Concomitant With Radiation Therapy and Temozolomide for the Treatment of Newly Diagnosed Glioblastoma

Conditions
-----------------
Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Device: Optune®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of GBM according to WHO classification criteria. Age ≥ 22 years in US and Age ≥ 18 years in Ex-US Recovered from maximal debulking surgery, if applicable (gross total resection, partial resection, and biopsy-only patients are all acceptable) Planned treatment with RT/TMZ followed by TTFields and maintenance TMZ (150-200 mg/m2 daily x 5 d, q28 days) Karnofsky performance status ≥ 70 Life expectancy ≥ least 3 months 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. All patients must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted. Stable or decreasing dose of corticosteroids for the last 7 days prior to randomization, if applicable. Concomitant RT with TMZ treatment planned to start no later than 8 weeks from surgery Women of childbearing potential must have a negative β-HCG pregnancy test documented within 14 days prior to registration Is able to have MRI with contrast of the brain Exclusion Criteria: Progressive disease (per investigator's assessment) Infratentorial or leptomeningeal disease Participation in another clinical treatment study during the pre-treatment and/or the treatment phase of the study Pregnancy or breast-feeding. Significant co-morbidities at baseline which would preclude maintenance RT or TMZ treatment, as determined by the investigator: Thrombocytopenia (platelet count < 100 x 103/μL) Neutropenia (absolute neutrophil count < 1.5 x 103/μL) CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting) Significant liver function impairment - AST or ALT > 3 times the upper limit of normal Total bilirubin > 1.5 x upper limit of normal Significant renal impairment (serum creatinine > 1.7 mg/dL, or > 150 µmol/l) 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 Implanted pacemaker, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias. Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness) History of hypersensitivity reaction to TMZ or a history of hypersensitivity to DTIC. Any other cytotoxic or biologic anti-tumor therapy received prior to enrollment will be considered exclusion. Admitted to an institution by administrative or court order. Known allergies to medical adhesives or hydrogel A skull defect (such as, missing bone with no replacement) Prior radiation treatment to the brain for the treatment of GBM Any serious surgical/post-operative condition that may risk the patient according to the investigator Standard TTFields exclusion criteria include Active implanted medical devices Bullet fragments Skull defects

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomly assigned equally to one of two groups: a. Treatment arm I: Patients receive TTFields at 200 kHz to the brain using the Optune® System together with RT and TMZ, followed by maintenance TMZ concomitant with the Optune® treatment. Treatment arm II: Patients receive RT and TMZ alone, followed by maintenance TMZ concomitant with TTFields at 200 kHz to the brain using the Optune®.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optune® + RT + TMZ for 6 weeks<br>Optune® + RT + TMZ for 6 weeks, followed by Optune® + TMZ until the tumor progresses. Optune treatment is maintained until second disease progression or 24 months. | Device: Optune®<br>* Optune® is a commercial, portable, battery-operated device intended for continuous home use, which delivers TTFields at a frequency of 200kHz to the brain by means of insulated transducer arrays. The Optune® device produces electric forces intended to disrupt cancer cell division. In treatment arm I, the patient starts Optune® concurrently with RT/TMZ for 6 weeks, followed by Optune® + TMZ until second disease progression. In treatment arm II, the patient starts RT/TMZ for 6 weeks, followed by Optune® + TMZ until second disease progression. The study treatment plan will continue for 24 months, if no tumor progression.<br>|
| Active Comparator: RT +TMZ for 6 weeks<br>RT +TMZ for 6 weeks followed by Optune® + TMZ until the tumor progresses. Optune treatment is maintained until second disease progression or 24 months. | Device: Optune®<br>* Optune® is a commercial, portable, battery-operated device intended for continuous home use, which delivers TTFields at a frequency of 200kHz to the brain by means of insulated transducer arrays. The Optune® device produces electric forces intended to disrupt cancer cell division. In treatment arm I, the patient starts Optune® concurrently with RT/TMZ for 6 weeks, followed by Optune® + TMZ until second disease progression. In treatment arm II, the patient starts RT/TMZ for 6 weeks, followed by Optune® + TMZ until second disease progression. The study treatment plan will continue for 24 months, if no tumor progression.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Survival will be measured from the time of randomization until date patient is alive. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS will be measured from the date of randomization to the date of progression. | 5 years | 
| 1- and 2-year survival rates | The analyses will be performed based on estimated proportions of patients who are on study at 12 and 24 months in both arms of the study. | 5 years | 
| Overall Radiological response (ORR) | The analyses will be performed based on the RANO criteria, and comparison between the rates of response. | 5 years | 
| Next progression-free survival (PFS2) | PFS2 will be measured from the time of randomization to second tumor progression. | 5 years | 
| Progression-free survival at 6 (PFS6) and 12 months (PFS12) | The analyses will be estimated proportions of patients who are progression-free at 6 and 12 months in both arms of the study. | 5 years | 
| Severity and frequency of adverse events | The analyses will be performed based on the incidence, severity, frequency of adverse events, and their association with study treatments. | 5 years | 
| Pathological changes in resected GBM tumors following study treatments | Pathological changes in the tumors and also underwent another surgical resection while on the study. | 5 years | 
| Quality of Life EORTC Questionnaire | The analyses will be assessed using the EORTC QLQ C-30 questionnaire with BN-20 (brain symptom) supplement. | 5 years | 
| Dependence of overall survival on TTFields dose at the tumor | Examining the dependence of overall survival on TTFields dose delivered to the tumor bed will be performed in both the treatment and control arms. | 5 years | 
| The NANO scale | The Neurological assessment in Neuro-Oncology will be assessed using the NANO scale questionnaire and per RANO criteria. | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GBM