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

NCT00916409 | Completed Phase 3 DMC

• 1 other identifier: EF-14
• Study Type: interventional
• Target: 700
• Locations: 12 countries
• Sites: 89

Brief Summary

The study is a prospective, randomly controlled pivotal trial, designed to test the efficacy and safety of a medical device, the NovoTTF-100A, as an adjuvant to the best standard of care in the treatment of newly diagnosed GBM patients. The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

Conditions

Glioblastoma Multiforme

Keywords

Glioblastoma Multiforme; Glioblastoma; GBM; Brain tumor; Treatment; Minimal toxicity; Newly Diagnosed; TTFields; Tumor Treating Fields; NovoCure

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS) time

  5 years

Secondary Outcomes (1)

• Overall survival (OS)

  5 years

Study Arms (2)

NovoTTF-100A device in combination with Temozolomide

EXPERIMENTAL

patients will be treated continuously with the NovoTTF-100A device, in addition to Temozolomide. NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. The treatment enables the patient to maintain regular daily routine.

Device: NovoTTF-100A device

Temozolomide alone, as the best known standard of care

ACTIVE COMPARATOR

Patients will be treated with Temozolomide, as the best known standard of care for Glioblastoma Multiforme patients.

Drug: Temozolomide

Interventions

NovoTTF-100A device DEVICE

patients will be treated continuously with the NovoTTF-100A device, in addition to Temozolomide. NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. The treatment enables the patient to maintain regular daily routine.

NovoTTF-100A device in combination with Temozolomide

Temozolomide DRUG

maintenance Temozolomide will be administered according to the approved dosing scheme as follows: Maintenance Phase Cycle 1: Four weeks after completing the Temozolomide + Radiotherapy phase, Temozolomide is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. Cycles 2-6: At the start of Cycle 2, the dose is escalated to 200 mg/m2, if the CTC non-hematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, and the platelet count is ≥ 100 x 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.

Temozolomide alone, as the best known standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathological evidence of GBM using WHO classification criteria.
• \> 18 years of age.
• Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):
• Patients may enroll in the study if received Gliadel wafers before entering the trial
• Minimal dose for concomitant radiotherapy is 45 Gy
• Karnofsky scale ≥ 70
• Life expectancy at least 3 months
• Participants of childbearing age must use effective contraception.
• All patients must sign written informed consent.
• Treatment start date at least 4 weeks out from surgery.
• 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.

You may not qualify if:

• Progressive disease (according to MacDonald Criteria). If pseudoprogression is suspected, additional imaging studies must be performed to rule out true progression.
• Actively participating in another clinical treatment trial
• Pregnant
• Significant co-morbidities at baseline which would prevent maintenance Temozolomide treatment:
• 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 \> upper limit of normal
• Significant renal impairment (serum creatinine \> 1.7 mg/dL)
• Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
• Infra-tentorial tumor
• Evidence of increased intracranial pressure (midline shift \> 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness)
• History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity to DTIC.

Sponsors & Collaborators

• NovoCure Ltd.: lead

Study Sites (89)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-3410, United States

Location

Barrow Neurology Clinics

Phoenix, Arizona, 85013, United States

Location

City of Hope

Duarte, California, 91010-3000, United States

Location

University of California San Diego Moores Cancer Center (UCSD)

La Jolla, California, 92093, United States

Location

University of Southern California (USC)

Los Angeles, California, 90033, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

UF Health Cancer Center at Orlando Health

Orlando, Florida, 32806, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, 33612, United States

Location

Emory University, Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

University of Illinois at Chicago (UIC)

Chicago, Illinois, 60612, United States

Location

University of Kentucky, Markey Cancer Center

Lexington, Kentucky, 40536-0093, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40202, United States

Location

Maine Medical Center

Scarborough, Maine, 04074, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Lahey Clinic Medical Center

Burlington, Massachusetts, 01805, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Washington University School of Medicine, Division of Oncology

St Louis, Missouri, 63110, United States

Location

New Jersey Neuroscience Center - JFK Medical Center

Edison, New Jersey, 08818, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

Mount Sinai Medical Center, Department of Neurosurgery

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

The Ohio State University Arthur G. James Cancer Hospital and Solove Research Institute

Columbus, Ohio, 43210, United States

Location

Geisinger Health System

Danville, Pennsylvania, 17822, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Pennsylvania Hospital

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Medical Center (UPMC)

Pittsburgh, Pennsylvania, 15232, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75235-8808, United States

Location

Baylor

Dallas, Texas, 75246, United States

Location

Methodist Hospital

Houston, Texas, 77030, United States

Location

Methodist Neurological Institute

Houston, Texas, 77030, United States

Location

The University of Texas Health Science Center at Houston (UTHSC)

Houston, Texas, 77030, United States

Location

Scott and White Healthcare

Temple, Texas, 76508, United States

Location

Memorial Hermann The Woodlands

The Woodlands, Texas, 77380, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Swedish Neuroscience Institute

Seattle, Washington, 98122, United States

Location

University of Washington/Seattle Cancer Care Alliance

Seattle, Washington, 98195, United States

Location

University Hospital Graz

Graz, Austria

Location

Medical University of Vienna

Vienna, Austria

Location

SMZ-Süd/Kaiser-Franz-Josef-Spital

Vienna, Austria

Location

Tom Baker Cancer Center

Calgary, Alberta, T2N 4N2, Canada

Location

CancerCare Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

Location

Juravinski Cancer Centre

Hamilton, Ontario, L8V5C2, Canada

Location

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, K1H 8L6, Canada

Location

Notre-Dame Hospital (CHUM)

Montreal, Quebec, H2L 4 M1, Canada

Location

Montreal Neurological Institute

Montreal, Quebec, H3A 2B4, Canada

Location

McGill - Gerald Bronfman Centre for Clinical Research in Oncology -

Montreal, Quebec, H3T 1E2, Canada

Location

(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Na Homolce Hospital

Prague, Czechia

Location

CHU Amiens Sud-Salouel

Amiens, France

Location

CHU Angers

Angers, France

Location

Hôpital Saint André Centre Hospitalier Universitaire (CHU) des Hôpitaux de Bordeaux

Bordeaux, France

Location

Hospital of Neurology Pierre Wertheimer

Lyon, France

Location

Group Hospitals Pitie-Salpetriere

Paris, France

Location

Centre Hospitalo-Universitaire de Toulouse Purpan

Toulouse, France

Location

University Medical Center Hamburg-Eppendorf

Hamburg, Germany

Location

Medical University Heidelberg

Heidelberg, Germany

Location

University Hospital of Schleswig-Holstein

Kiel, Germany

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel

Location

Az. Ospedaliero-Universitaria - Ospedali Riuniti

Ancona, Italy

Location

Ospedale Lecco

Lecco, Italy

Location

C. Besta Neurological Institute

Milan, Italy

Location

Foundation Hospital Greater Policlinico

Milan, Italy

Location

Istituti Fisioterapici Ospitalieri - Istituto Nazionale dei Tumori Regina Elena

Rome, Italy

Location

Asan Medical Center

Asan, South Korea

Location

Yeungnam University Hospital

Daegu, South Korea

Location

Chungnam National University Hospital (CNUH)

Daejeon, South Korea

Location

Samsung Medical Center (SMC)

Seoul, South Korea

Location

Seoul National University Bundang Hospital (SNUBH)

Seoul, South Korea

Location

Seoul National University Hospital (SNUH)

Seoul, South Korea

Location

The Catholic University of Korea, Seoul St. Mary's Hospital (CMC Seoul)

Seoul, South Korea

Location

Yonsei University Severance Hospital (YUHS)

Seoul, South Korea

Location

Ajou University Hospital (AUH)

Suwon, South Korea

Location

Hospital Universitari Germans Trias i Pujol

Badalona, Spain

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Universitari de Bellvitge-ICO Duran i Reynals

Barcelona, Spain

Location

Fundacion Jimenes Diaz

Madrid, Spain

Location

Hospital 12 de Octubre, Servicio de Oncología Médica

Madrid, Spain

Location

Hospital Clinico San Carlos

Madrid, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Spain

Location

Clínica Universidad de Navarra

Pamplona, Spain

Location

Karolinska Institute

Stockholm, Sweden

Location

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Switzerland

Location

UniversitätsSpital Zürich

Zurich, Switzerland

Location

Related Publications (14)

• Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95. doi: 10.1158/0008-5472.can-04-0083.

  PMID: 15126372 BACKGROUND

• Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. doi: 10.1073/pnas.0702916104. Epub 2007 Jun 5.

  PMID: 17551011 BACKGROUND

• Salzberg M, Kirson E, Palti Y, Rochlitz C. A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008 Jul;31(7):362-5. doi: 10.1159/000137713. Epub 2008 Jun 24.

  PMID: 18596382 BACKGROUND

• Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub 2009 Apr 23.

  PMID: 19387848 BACKGROUND

• Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009 Jan 8;9:1. doi: 10.1186/1756-6649-9-1.

  PMID: 19133110 BACKGROUND

• Ram Z, Kim CY, Hottinger AF, Idbaih A, Nicholas G, Zhu JJ. Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial. Front Oncol. 2021 Sep 27;11:671972. doi: 10.3389/fonc.2021.671972. eCollection 2021.

  PMID: 34692470 DERIVED

• Kim CY, Paek SH, Nam DH, Chang JH, Hong YK, Kim JH, Kim OL, Kim SH. Tumor treating fields plus temozolomide for newly diagnosed glioblastoma: a sub-group analysis of Korean patients in the EF-14 phase 3 trial. J Neurooncol. 2020 Feb;146(3):399-406. doi: 10.1007/s11060-019-03361-2. Epub 2020 Feb 4.

  PMID: 32020470 DERIVED

• Ballo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Z, Toms S. Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial. Int J Radiat Oncol Biol Phys. 2019 Aug 1;104(5):1106-1113. doi: 10.1016/j.ijrobp.2019.04.008. Epub 2019 Apr 23.

  PMID: 31026557 DERIVED

• Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol. 2019 Jan;141(2):467-473. doi: 10.1007/s11060-018-03057-z. Epub 2018 Dec 1.

  PMID: 30506499 DERIVED

• Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):495-504. doi: 10.1001/jamaoncol.2017.5082.

  PMID: 29392280 DERIVED

• Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718.

  PMID: 29260225 DERIVED

• Kesari S, Ram Z; EF-14 Trial Investigators. Tumor-treating fields plus chemotherapy versus chemotherapy alone for glioblastoma at first recurrence: a post hoc analysis of the EF-14 trial. CNS Oncol. 2017 Jul;6(3):185-193. doi: 10.2217/cns-2016-0049. Epub 2017 Apr 12.

  PMID: 28399638 DERIVED

• Meletath SK, Pavlick D, Brennan T, Hamilton R, Chmielecki J, Elvin JA, Palma N, Ross JS, Miller VA, Stephens PJ, Snipes G, Rajaram V, Ali SM, Melguizo-Gavilanes I. Personalized Treatment for a Patient With a BRAF V600E Mutation Using Dabrafenib and a Tumor Treatment Fields Device in a High-Grade Glioma Arising From Ganglioglioma. J Natl Compr Canc Netw. 2016 Nov;14(11):1345-1350. doi: 10.6004/jnccn.2016.0145.

  PMID: 27799506 DERIVED

• Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669.

  PMID: 26670971 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms

Interventions

Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Roger Stupp, MD

  University Hospital, Zürich

  STUDY DIRECTOR

• Philip H. Gutin, MD

  Memorial Sloan Kettering Cancer Center

  STUDY DIRECTOR

• Eric T. Wong, MD

  Beth Israel Deaconess Medical Center

  STUDY DIRECTOR

• Herbert H. Engelhard, MD, PhD

  University of Illinois at Chicago

  STUDY DIRECTOR

• Manfred Westphal, Prof. MD

  Universitätsklinikum Hamburg-Eppendorf

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2009
• First Posted: June 9, 2009
• Study Start: June 1, 2009
• Primary Completion: December 1, 2016
• Study Completion: March 1, 2017
• Last Updated: April 10, 2017

Record last verified: 2017-04

Locations

CH (2); AU (3); ES (9); CA (8); IL (1); FR (6); CZ (1); IT (5); DE (3); KR (9); SE (1); US (41)