Glioblastoma MultiformePhase 3NCT00916409
Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM)
A Phase 3 study testing NovoTTF-100A device and Temozolomide in people with Glioblastoma Multiforme, run by NovoCure Ltd. at 89 sites in 12 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma Multiforme
- What is being tested?
- NovoTTF-100A device and Temozolomide
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 700 participants
- Where
- 89 sitesin 12 countries
- Study dates
- Jun 2009to Mar 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- Any additional treatments received prior to enrollment will be considered an exclusion.
- Minimal dose for concomitant radiotherapy is 45 Gy
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- 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.
Who cannot join
- 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)
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- 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.
Trial locations and contacts
89 sites in 12 countries.
89 sites in 12 countries
United States41 sites
Emory University, Winship Cancer Institute
Atlanta, Georgia, 30322
University of Colorado Denver
Aurora, Colorado, 80045
The Johns Hopkins Hospital
Baltimore, Maryland, 21287
University of Alabama at Birmingham
Birmingham, Alabama, 35294-3410
Tufts Medical Center
Boston, Massachusetts, 02111
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Lahey Clinic Medical Center
Burlington, Massachusetts, 01805
University of North Carolina
Chapel Hill, North Carolina, 27599
University of Virginia Health System
Charlottesville, Virginia, 22908
University of Illinois at Chicago (UIC)
Chicago, Illinois, 60612
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, 44195
The Ohio State University Arthur G. James Cancer Hospital and Solove Research Institute
Columbus, Ohio, 43210
UT Southwestern Medical Center
Dallas, Texas, 75235-8808
Baylor
Dallas, Texas, 75246
Geisinger Health System
Danville, Pennsylvania, 17822
Henry Ford Health System
Detroit, Michigan, 48202
City of Hope
Duarte, California, 91010-3000
New Jersey Neuroscience Center - JFK Medical Center
Edison, New Jersey, 08818
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, 07601
Methodist Hospital
Houston, Texas, 77030
Methodist Neurological Institute
Houston, Texas, 77030
The University of Texas Health Science Center at Houston (UTHSC)
Houston, Texas, 77030
University of California San Diego Moores Cancer Center (UCSD)
La Jolla, California, 92093
University of Kentucky, Markey Cancer Center
Lexington, Kentucky, 40536-0093
University of Southern California (USC)
Los Angeles, California, 90033
Norton Cancer Institute
Louisville, Kentucky, 40202
Weill Cornell Medical College
New York, New York, 10021
Mount Sinai Medical Center, Department of Neurosurgery
New York, New York, 10029
Columbia University Medical Center
New York, New York, 10032
UF Health Cancer Center at Orlando Health
Orlando, Florida, 32806
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Pennsylvania Hospital
Philadelphia, Pennsylvania, 19104
Barrow Neurology Clinics
Phoenix, Arizona, 85013
University of Pittsburgh Medical Center (UPMC)
Pittsburgh, Pennsylvania, 15232
Maine Medical Center
Scarborough, Maine, 04074
Swedish Neuroscience Institute
Seattle, Washington, 98122
University of Washington/Seattle Cancer Care Alliance
Seattle, Washington, 98195
Washington University School of Medicine, Division of Oncology
St Louis, Missouri, 63110
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, 33612
Scott and White Healthcare
Temple, Texas, 76508
Memorial Hermann The Woodlands
The Woodlands, Texas, 77380
South Korea9 sites
Asan Medical Center
Asan
Yeungnam University Hospital
Daegu
Chungnam National University Hospital (CNUH)
Daejeon
Samsung Medical Center (SMC)
Seoul
Seoul National University Bundang Hospital (SNUBH)
Seoul
Seoul National University Hospital (SNUH)
Seoul
The Catholic University of Korea, Seoul St. Mary's Hospital (CMC Seoul)
Seoul
Yonsei University Severance Hospital (YUHS)
Seoul
Ajou University Hospital (AUH)
Suwon
Spain9 sites
Hospital Universitari Germans Trias i Pujol
Badalona
Hospital Clinic i Provincial de Barcelona
Barcelona
Hospital del Mar
Barcelona
Hospital Universitari de Bellvitge-ICO Duran i Reynals
Barcelona
Fundacion Jimenes Diaz
Madrid
Hospital 12 de Octubre, Servicio de Oncología Médica
Madrid
Hospital Clinico San Carlos
Madrid
Hospital Universitario Ramon y Cajal
Madrid
Clínica Universidad de Navarra
Pamplona
Canada8 sites
Tom Baker Cancer Center
Calgary, Alberta, T2N 4N2
Juravinski Cancer Centre
Hamilton, Ontario, L8V5C2
Notre-Dame Hospital (CHUM)
Montreal, Quebec, H2L 4 M1
Montreal Neurological Institute
Montreal, Quebec, H3A 2B4
McGill - Gerald Bronfman Centre for Clinical Research in Oncology -
Montreal, Quebec, H3T 1E2
The Ottawa Hospital Cancer Centre
Ottawa, Ontario, K1H 8L6
(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie
Sherbrooke, Quebec, J1H 5N4
CancerCare Manitoba
Winnipeg, Manitoba, R3E 0V9
France6 sites
CHU Amiens Sud-Salouel
Amiens
CHU Angers
Angers
Hôpital Saint André Centre Hospitalier Universitaire (CHU) des Hôpitaux de Bordeaux
Bordeaux
Hospital of Neurology Pierre Wertheimer
Lyon
Group Hospitals Pitie-Salpetriere
Paris
Centre Hospitalo-Universitaire de Toulouse Purpan
Toulouse
Italy5 sites
Az. Ospedaliero-Universitaria - Ospedali Riuniti
Ancona
Ospedale Lecco
Lecco
C. Besta Neurological Institute
Milan
Foundation Hospital Greater Policlinico
Milan
Istituti Fisioterapici Ospitalieri - Istituto Nazionale dei Tumori Regina Elena
Rome
Austria3 sites
University Hospital Graz
Graz
Medical University of Vienna
Vienna
SMZ-Süd/Kaiser-Franz-Josef-Spital
Vienna
Germany3 sites
University Medical Center Hamburg-Eppendorf
Hamburg
Medical University Heidelberg
Heidelberg
University Hospital of Schleswig-Holstein
Kiel
Switzerland2 sites
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne
UniversitätsSpital Zürich
Zurich
About this study
Official title: A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients With Newly Diagnosed GBM.
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.
Read the detailed description
PAST CLINICAL EXPERIENCE:
The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has been tested in a large prospective, randomized trial, in recurrent GBM. The outcome of subjects treated with the NovoTTF-100A device was compared to those treated with an effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A subjects had comparable overall survival to subjects receiving the best available chemotherapy in the US today. Similar results showing comparability of NovoTTF-100A to BSC chemotherapy were seen in all secondary endpoints.
Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer side effects in general, significantly fewer treatment related side effects, and significantly lower gastrointestinal, hematological and infectious adverse events compared to controls. The only device-related adverse events seen were a mild to moderate skin irritation beneath the device electrodes. Finally, quality of life measures were better in NovoTTF-100A subjects as a group when compared to subjects receiving effective best standard of care chemotherapy.
In a small scale pilot trial in newly diagnosed GBM patients, the treatment was well tolerated and suggested that NovoTTF-100A may improve time to disease progression and overall survival of newly diagnosed GBM patients. Although the number of patients in the pilot trial was small, The FDA has determined that the data gathered so far warrant testing of NovoTTF-100A treatment as a possible therapy for patients with newly diagnosed GBM.
DESCRIPTION OF THE TRIAL:
All patients included in this trial are newly diagnosed GBM patients who underwent a biopsy or surgery (with or without Gliadel wafers), followed by radiation therapy in combination with Temozolomide chemotherapy. In addition, all patients must meet all eligibility criteria.
Eligible patients will be randomly assigned to one of two groups:
- Treatment with the NovoTTF-100A device in combination with Temozolomide chemotherapy.
- Treatment with Temozolomide alone, as the best known standard of care.
Patients will be randomized at a 2:1 ratio (2 of every three patients who participate in the trial will be treated with the NovoTTF-100A device). Baseline tests will be performed in patients enrolled in both arms, including specific genetic tests done using tumor samples obtained during their initial surgery. If assigned to the NovoTTF-100A in combination with Temozolomide group, the patients will be treated continuously with the device until second progression. They will also receive temozolomide and possibly a second line treatment that can be one of the following: re-operation, local radiotherapy (gamma-knife), a second line of chemotherapy or a combination of the above.
NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. Electrode array placement will require shaving of the scalp before and frequently during the treatment. After an initial short visit to the clinic for training and monitoring, patients will be released to continue treatment at home where they can maintain their regular daily routine.
During the trial, regardless of which treatment group the patient was assigned to, he or she will need to return once every month to the clinic where an examination by a physician and a routine laboratory examinations will be done. These routine visits will continue for as long as the patient's disease is not progressing for the second time under the study treatment. If such occurs, patients will need to return once per month for two more months to the clinic for similar follow up examinations.
During the visits to the clinic patients will be examined physically and neurologically. Additionally, routine blood tests will be performed. A routine MRI of the head will be performed at baseline and every second month thereafter, until second progression. After this follow up plan, patients will be contacted once per month by telephone to answer basic questions about their health status.
SCIENTIFIC BACKGROUND:
Electric fields exert forces on electric charges similar to the way a magnet exerts forces on metallic particles within a magnetic field. These forces cause movement and rotation of electrically charged biological building blocks, much like the alignment of metallic particles seen along the lines of force radiating outwards from a magnet.
Electric fields can also cause muscles to twitch and if strong enough may heat tissues. TTFields are alternating electric fields of low intensity. This means that they change their direction repetitively many times a second. Since they change direction very rapidly (200 thousand times a second), they do not cause muscles to twitch, nor do they have any effects on other electrically activated tissues in the body (brain, nerves and heart). Since the intensities of TTFields in the body are very low, they do not cause heating.
The breakthrough finding made by NovoCure was that finely tuned alternating fields of very low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are multiplying, TTFields cause the building blocks of these cells to move and pile up in such a way that the cells physically explode. In addition, cancer cells also contain miniature building blocks which act as tiny motors in moving essential parts of the cells from place to place. TTFields cause these tiny motors to fall apart since they have a special type of electric charge.
As a result of these two effects, cancer tumor growth is slowed and can even reverse after continuous exposure to TTFields.
Other cells in the body (normal healthy tissues) are affected much less than cancer cells since they multiply at a much slower rate if at all. In addition TTFields can be directed to a certain part of the body, leaving sensitive areas out of their reach.
In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very few side effects and promising affectivity in slowing or reversing this disease.
- Conditions
- Glioblastoma Multiforme
- Being tested
- NovoTTF-100A device, Temozolomide
- Keywords
- Glioblastoma Multiforme, Glioblastoma, GBM, Brain tumor, Treatment, Minimal toxicity, Newly Diagnosed, TTFields, Tumor Treating Fields, NovoCure
- Medical subject headings
- Glioblastoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NovoTTF-100A deviceDevice
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.
TemozolomideDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS) time
Measured: 5 years
Secondary outcomes (1)
Overall survival (OS)
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2009 (estimated)
- Study startJun 2009
- Primary completionDec 2016
- Study completionMar 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Glioblastoma MultiformeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 700 participants (estimated)
Sponsor and investigators
- Lead sponsor
- NovoCure Ltd.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Roger Stupp, MD, Study director, University Hospital, ZürichPhilip H. Gutin, MD, Study director, Memorial Sloan Kettering Cancer CenterEric T. Wong, MD, Study director, Beth Israel Deaconess Medical CenterHerbert H. Engelhard, MD, PhD, Study director, University of Illinois ChicagoManfred Westphal, Prof. MD, Study director, Universitätsklinikum Hamburg-Eppendorf
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00916409
- Sponsor's protocol ID
- EF-14
- Status last verified
- Apr 2017
- First submitted
- 5 Jun 2009
- Last updated
- 10 Apr 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 15126372Kirson 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.
PubMed 17551011Salzberg 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.
PubMed 18596382Kirson 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.
PubMed 19387848Kirson 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.
PubMed 19133110Ram 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.
PubMed 34692470Kim 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.
PubMed 32020470Ballo 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.
PubMed 31026557Toms 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.
PubMed 30506499Taphoorn 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.
PubMed 29392280Stupp 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.
PubMed 29260225Kesari 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.
PubMed 28399638Meletath 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.
PubMed 27799506Stupp 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.
PubMed 26670971
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients With Newly Diagnosed GBM.
- ClinicalTrials.gov ID
- NCT00916409
- Acronym / sponsor ID
- EF-14
- Conditions
- Glioblastoma Multiforme
- Keywords
- Glioblastoma Multiforme, Glioblastoma, GBM, Brain tumor, Treatment, Minimal toxicity, Newly Diagnosed, TTFields
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 700 participants (estimated)
- Lead sponsor
- NovoCure Ltd.Industry (pharma, biotech, devices)
- Study start
- Jun 2009
- Primary completion
- Dec 2016 (actual)
- Study completion
- Mar 2017 (actual)
- First posted
- 9 Jun 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PAST CLINICAL EXPERIENCE:
The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has been tested in a large prospective, randomized trial, in recurrent GBM. The outcome of subjects treated with the NovoTTF-100A device was compared to those treated with an effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A subjects had comparable overall survival to subjects receiving the best available chemotherapy in the US today. Similar results showing comparability of NovoTTF-100A to BSC chemotherapy were seen in all secondary endpoints.
Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer side effects in general, significantly fewer treatment related side effects, and significantly lower gastrointestinal, hematological and infectious adverse events compared to controls. The only device-related adverse events seen were a mild to moderate skin irritation beneath the device electrodes. Finally, quality of life measures were better in NovoTTF-100A subjects as a group when compared to subjects receiving effective best standard of care chemotherapy.
In a small scale pilot trial in newly diagnosed GBM patients, the treatment was well tolerated and suggested that NovoTTF-100A may improve time to disease progression and overall survival of newly diagnosed GBM patients. Although the number of patients in the pilot trial was small, The FDA has determined that the data gathered so far warrant testing of NovoTTF-100A treatment as a possible therapy for patients with newly diagnosed GBM.
DESCRIPTION OF THE TRIAL:
All patients included in this trial are newly diagnosed GBM patients who underwent a biopsy or surgery (with or without Gliadel wafers), followed by radiation therapy in combination with Temozolomide chemotherapy. In addition, all patients must meet all eligibility criteria.
Eligible patients will be randomly assigned to one of two groups:
- Treatment with the NovoTTF-100A device in combination with Temozolomide chemotherapy.
- Treatment with Temozolomide alone, as the best known standard of care.
Patients will be randomized at a 2:1 ratio (2 of every three patients who participate in the trial will be treated with the NovoTTF-100A device). Baseline tests will be performed in patients enrolled in both arms, including specific genetic tests done using tumor samples obtained during their initial surgery. If assigned to the NovoTTF-100A in combination with Temozolomide group, the patients will be treated continuously with the device until second progression. They will also receive temozolomide and possibly a second line treatment that can be one of the following: re-operation, local radiotherapy (gamma-knife), a second line of chemotherapy or a combination of the above.
NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. Electrode array placement will require shaving of the scalp before and frequently during the treatment. After an initial short visit to the clinic for training and monitoring, patients will be released to continue treatment at home where they can maintain their regular daily routine.
During the trial, regardless of which treatment group the patient was assigned to, he or she will need to return once every month to the clinic where an examination by a physician and a routine laboratory examinations will be done. These routine visits will continue for as long as the patient's disease is not progressing for the second time under the study treatment. If such occurs, patients will need to return once per month for two more months to the clinic for similar follow up examinations.
During the visits to the clinic patients will be examined physically and neurologically. Additionally, routine blood tests will be performed. A routine MRI of the head will be performed at baseline and every second month thereafter, until second progression. After this follow up plan, patients will be contacted once per month by telephone to answer basic questions about their health status.
SCIENTIFIC BACKGROUND:
Electric fields exert forces on electric charges similar to the way a magnet exerts forces on metallic particles within a magnetic field. These forces cause movement and rotation of electrically charged biological building blocks, much like the alignment of metallic particles seen along the lines of force radiating outwards from a magnet.
Electric fields can also cause muscles to twitch and if strong enough may heat tissues. TTFields are alternating electric fields of low intensity. This means that they change their direction repetitively many times a second. Since they change direction very rapidly (200 thousand times a second), they do not cause muscles to twitch, nor do they have any effects on other electrically activated tissues in the body (brain, nerves and heart). Since the intensities of TTFields in the body are very low, they do not cause heating.
The breakthrough finding made by NovoCure was that finely tuned alternating fields of very low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are multiplying, TTFields cause the building blocks of these cells to move and pile up in such a way that the cells physically explode. In addition, cancer cells also contain miniature building blocks which act as tiny motors in moving essential parts of the cells from place to place. TTFields cause these tiny motors to fall apart since they have a special type of electric charge.
As a result of these two effects, cancer tumor growth is slowed and can even reverse after continuous exposure to TTFields.
Other cells in the body (normal healthy tissues) are affected much less than cancer cells since they multiply at a much slower rate if at all. In addition TTFields can be directed to a certain part of the body, leaving sensitive areas out of their reach.
In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very few side effects and promising affectivity in slowing or reversing this disease.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| NovoTTF-100A device in combination with Temozolomide | Experimental | Device: NovoTTF-100A devicepatients 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. |
| Temozolomide alone, as the best known standard of care | Active comparator | Drug: TemozolomidePatients will be treated with Temozolomide, as the best known standard of care for Glioblastoma Multiforme patients. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Pathological evidence of GBM using WHO classification criteria.
- > 18 years of age.
- Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):
- Karnofsky scale ≥ 70
- Life expectancy at least 3 months
Key exclusion criteria (14 listed)
- 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:
- Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NovoTTF-100A devicepatients 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 in combination with Temozolomide |
| Temozolomidemaintenance 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. | Drug | Temozolomide alone, as the best known standard of care |
Primary outcome
Progression Free Survival (PFS) time
Time frame: 5 years
1 secondary outcome
Overall survival (OS)
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Apr 2017.
- Background: PubMed 15126372Kirson 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.
- Background: PubMed 17551011Kirson 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.
- Background: PubMed 18596382Salzberg 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.
- Background: PubMed 19387848Kirson 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.
- Background: PubMed 19133110Kirson 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.
- Derived from this study: PubMed 34692470Ram 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.
- Derived from this study: PubMed 32020470Kim 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.
- Derived from this study: PubMed 31026557Ballo 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.
- Derived from this study: PubMed 30506499Toms 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.
- Derived from this study: PubMed 29392280Taphoorn 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.
- Derived from this study: PubMed 29260225Stupp 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.
- Derived from this study: PubMed 28399638Kesari 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roger Stupp, MD study director
University Hospital, Zürich
Philip H. Gutin, MD study director
Memorial Sloan Kettering Cancer Center
Eric T. Wong, MD study director
Beth Israel Deaconess Medical Center
89 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing NovoTTF-100A device and Temozolomide in people with Glioblastoma Multiforme, run by NovoCure Ltd. at 89 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 89 sites in United States, South Korea, Spain, Canada, France and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) time (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00916409, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2017.