Clinical trial NCT04471844: Pivotal, Randomized, Open-label Study of Optune® (Tumor Treating Fields) Concomitant with RT & TMZ for the Treatment of Newly Diagnosed GBM
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Glioblastoma Multiforme
Keywords: GBM
Lead sponsor: NovoCure Ltd.
Sponsor class: INDUSTRY
First posted: 2020-07-15
Enrollment: 982
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomly assigned equally to one of two groups:

1. 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.
2. 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®.
Primary purpose: TREATMENT

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:

1. 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.
2. 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 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 10 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 site and sponsor.

Subjects will be required to return to the clinic per the study protocol.

After the second disease progression, subjects will return to the clinic for one final visit approximately 30 days after the last treatment with Optune® or after second disease progression, the latter of the two per protocol.

After completing active participation in the study, subjects will be contacted once per month by telephone to answer basic questions about their health status.

Eligibility criteria: \*Age Limits - 18 years or older outside of the US, 22 years or older within the US.

Inclusion Criteria:

1. Histologically confirmed diagnosis of GBM according to WHO classification criteria.
2. Age ≥ 22 years in US and Age ≥ 18 years in Ex-US
3. Recovered from maximal debulking surgery, if applicable (gross total resection, partial resection, and biopsy-only patients are all acceptable)
4. Planned treatment with RT/TMZ followed by TTFields and maintenance TMZ (150-200 mg/m2 daily x 5 d, q28 days)
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. Stable or decreasing dose of corticosteroids for the last 7 days prior to randomization, if applicable.
10. Concomitant RT with TMZ treatment planned to start no later than 8 weeks from surgery
11. Women of childbearing potential must have a negative β-HCG pregnancy test documented within 14 days prior to randomization
12. Is able to have MRI with contrast of the brain

Exclusion Criteria:

1. Progressive disease (per investigator's assessment)
2. Infratentorial or leptomeningeal disease
3. Participation in another clinical treatment study during the pre-treatment and/or the treatment phase of the study
4. Pregnancy or breast-feeding.
5. Significant co-morbidities at baseline which would preclude maintenance RT or TMZ treatment, as determined by the investigator:

   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 \> 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. History of hypersensitivity reaction to TMZ or a history of hypersensitivity to DTIC.
9. Additional malignancies that are progressing or required active treatment in the last two years.
10. Admitted to an institution by administrative or court order.
11. Known allergies to medical adhesives or hydrogel
12. A skull defect (such as, missing bone with no replacement)
13. Prior radiation treatment to the brain for the treatment of GBM
14. Any serious surgical/post-operative condition that may put the participant at risk according to the investigator.
15. Standard TTFields exclusion criteria include

    1. Active implanted medical devices
    2. Bullet fragments
    3. Skull defects

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: 5 years
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 5 years
measure: 1- and 2-year survival rates
timeFrame: 5 years
measure: Overall Radiological response (ORR)
timeFrame: 5 years
measure: Next progression-free survival (PFS2)
timeFrame: 5 years
measure: Progression-free survival at 6 (PFS6) and 12 months (PFS12)
timeFrame: 5 years
measure: Severity and frequency of adverse events
timeFrame: 5 years
measure: Pathological changes in resected GBM tumors following study treatments
timeFrame: 5 years
measure: Quality of Life EORTC Questionnaire
timeFrame: 5 years
measure: Dependence of overall survival on TTFields dose at the tumor
timeFrame: 5 years
measure: The NANO scale
timeFrame: 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Grandview Cancer Center
state: Alabama
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic- Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Burbank
country: United States
facility: Providence St. Joseph Medical Center and The Roy and Patricia Disney Family Cancer Center
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Fullerton
country: United States
facility: TRIO - St. Jude Heritage Healthcare/St. Jude Medical Center
state: California
city: La Jolla
country: United States
facility: University of California at San Diego - Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Norris Comprehensive Cancer Center at USC
state: California
city: Los Angeles
country: United States
facility: Cedars - Sinai Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital - Hoag Cancer Center
state: California
city: Orange
country: United States
facility: St. Joseph Hospital of Orange
state: California
city: Orange
country: United States
facility: University of California - Irvine/UCI Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford University Cancer Institute
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital - X-Ray Medical Group Radiation Oncology
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Santa Monica
country: United States
facility: John Wayne Cancer Institute at St. John's Health Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center Anschutz
state: Colorado
city: Englewood
country: United States
facility: HCA Research Institute - Blue Sky Neurology - Denver
state: Colorado
city: Hartford
country: United States
facility: Hartford Healthcare Medical Group - Hartford Hospital The Gray Cancer Center
state: Connecticut
city: Boca Raton
country: United States
facility: Lynn Cancer Institute, Marcus Neuroscience Institute
state: Florida
city: Jacksonville
country: United States
facility: Baptist Health - Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Orlando
country: United States
facility: Orlando Health UF Health Cancer Center
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc
state: Florida
city: Atlanta
country: United States
facility: Piedmont Healthcare Brain Tumor Center
state: Georgia
city: Atlanta
country: United States
facility: The Emory Clinic - Emory Healthcare - Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital, Inc.
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Fort Wayne
country: United States
facility: Parkview Cancer Institute - Fort Wayne Radiation Oncology Associates
state: Indiana
city: Topeka
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville - James Graham Brown Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Baton Rouge
country: United States
facility: Mary Bird Cancer Center Neuromedical Center
state: Louisiana
city: New Orleans
country: United States
facility: LSU Health Sciences Center, New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: South Portland
country: United States
facility: Maine Medical Partners Neurology - Neurosurgery & Spine Associates
state: Maine
city: Baltimore
country: United States
facility: John Hopkins School of Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Chan Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital - Givens Brain Tumor Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Columbia
country: United States
facility: University of Missouri - Ellis Fischel Cancer Center
state: Missouri
city: Kansas City
country: United States
facility: Health Midwest Ventures Group, Inc - Sarah Cannon HCA Midwest Brain and Spine
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Edison
country: United States
facility: JFK Neuroscience Institute, HMH JFK University Medical Center
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center - John Theurer Cancer Center
state: New Jersey
city: Neptune
country: United States
facility: Jersey Shore University Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health System Brain Tumor Center
state: New York
city: New York
country: United States
facility: NYU Langone - Laura & Issac Perimutter Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai - Icahn School of Medicine
state: New York
city: New York
country: United States
facility: New York Presbyterian - Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Brain Tumor Program - UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Cancer Institute Radiation Oncology
state: North Carolina
city: Greenville
country: United States
facility: Vidant Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Forsyth Medical Center-Novant Health
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Comprehensive Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: The James Cancer Hospital and Solove Research Institute - Arthur G James Cancer Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU)
state: Oregon
city: Philadelphia
country: United States
facility: Neuroscience Center, Philadelphia - University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Health Network Cancer Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: MUSC Radiation Oncology Brain & Spine Tumor Program
state: South Carolina
city: Chattanooga
country: United States
facility: SCRI - Tennessee Oncology
state: Tennessee
city: Germantown
country: United States
facility: West Cancer Center - Germantown
state: Tennessee
city: Nashville
country: United States
facility: SCRI - Tennessee Oncology
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology Midtown - Austin Brain Tumor Center
state: Texas
city: Dallas
country: United States
facility: Baylor Charles A. Sammons Cancer Center - Baylor University Medical Center
state: Texas
city: Fort Worth
country: United States
facility: John Peter Smith Health Network - JPS Cancer Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: UT Health Mischer Neuroscience - Memorial Herman - UT Neurosciences
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center
state: Texas
city: Burlington
country: United States
facility: The University of Vermont Medical Center - University of Vermont Cancer Center
state: Vermont
city: Richmond
country: United States
facility: Massey Cancer Center - VCU Medical Center
state: Virginia
city: Seattle
country: United States
facility: UW Medical Center - Alvord Brain Tumor Center
state: Washington
city: Seattle
country: United States
facility: Swedish Health Services
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Cancer Institute
state: West Virginia
city: Innsbruck
country: Austria
facility: Innsbruck University Hospital
city: Linz
country: Austria
facility: Kepler University Hospital
city: Salzburg
country: Austria
facility: University Hospital Salzburg
city: Brussels
country: Belgium
facility: Hospital Erasme
city: Liège
country: Belgium
facility: University Hospital Liege - Sart Tilman
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver
state: British Columbia
city: Sydney
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute - Odette Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: CHUM Centre de Recherche
state: Quebec
city: Sherbrooke
country: Canada
facility: Universite de Sherbrooke - Sherbrooke Centre Hospitalier Universita
state: Quebec
city: Brno
country: Czechia
facility: Masaryk Memorial Cancer Institute
city: Pilsen
country: Czechia
facility: University Hospital Plzeň
city: Prague
country: Czechia
facility: Na Homolce Hospital
city: Angers
country: France
facility: Institut de cancérologie de l'Ouest
city: Bron
country: France
facility: Pierre Wertheimer Hospital
city: Marseille
country: France
facility: Hôpital la Timone
city: Nice
country: France
facility: University Hospital Nice
city: Paris
country: France
facility: Pitié-Salpêtrière University Hospital
city: Saint Herblain
country: France
facility: Institut de cancérologie de l'Ouest
city: Toulouse
country: France
facility: University Institute Cancer Toulouse Oncopole
city: Villejuif
country: France
facility: Gustave Roussy Institute
city: Berlin
country: Germany
facility: Charité Campus Virchow Clinic
city: Essen
country: Germany
facility: University Hospital Essen
city: Freiburg
country: Germany
facility: University Medical Center Freiburg
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Munich
country: Germany
facility: Rechts der Isar Hospital
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center - Ein Kerem
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Kanazawa-shi
country: Japan
facility: Kanazawa University Hospital
state: Ishikawa-Ken
city: Hidaka-shi
country: Japan
facility: Saitama Medical University International Medical Center
state: Saitama-Ken
city: Mitaka-shi
country: Japan
facility: Kyorin University Hospital
state: Tokyo-To
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo-To
city: Lausanne
country: Switzerland
facility: Lausanne University Hospital
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
Study officials:
References:
citation: Miller R, Niazi M, Russial O, Poiset S, Shi W. Tumor treating fields with radiation for glioblastoma: a narrative review. Chin Clin Oncol. 2022 Oct;11(5):40. doi: 10.21037/cco-22-90.
citation: Miller R, Song A, Ali A, Niazi M, Bar-Ad V, Martinez N, Glass J, Alnahhas I, Andrews D, Judy K, Evans J, Farrell C, Werner-Wasik M, Chervoneva I, Ly M, Palmer J, Liu H, Shi W. Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma. Front Oncol. 2022 Apr 29;12:896246. doi: 10.3389/fonc.2022.896246. eCollection 2022.