Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC).

• ClinicalTrials.gov Identifier: NCT02831959
• Recruitment Status: Active, not recruiting
• First Posted: July 13, 2016
• Last Update Posted: March 10, 2023
• Sponsor: NovoCure GmbH
• Information provided by (Responsible Party): NovoCure Ltd. ( NovoCure GmbH )

Study Description

Brief Summary:

The study is a prospective, randomized controlled phase III trial, to test the efficacy, safety and neurocognitive outcomes of advanced NSCLC patients, following stereotactic radiosurgery (SRS) for 1 inoperable brain metastasis or 2-10 brain metastases, treated with NovoTTF-200M and supportive treatment compared to supportive treatment alone. 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.

Condition or disease	Intervention/treatment	Phase
Brain Metastases From Non-small Cell Lung Cancer (NSCLC)	Device: NovoTTF-200M device; Other: Best Standard of Care	Phase 3

Detailed Description:

PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in combination with chemotherapies. TTFields have also shown to inhibit metastatic spread of malignant melanoma in in vivo experiment.

In a pilot study, 42 patients with advanced NSCLC who had tumor progression after at least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied to the chest and upper abdomen until disease progression (Pless M., et al., Lung Cancer 2011). Efficacy endpoints were remarkably high compared to historical data for pemetrexed alone.

In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active chemotherapy in extending survival, associated with minimal toxicity, good quality of life, and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a phase III trial of Optune® combined with maintenance temozolomide compared to maintenance temozolomide alone has shown that combined therapy led to a significant improvement in both progression free survival and overall survival in patients with newly diagnosed glioblastoma without the addition of high grade toxicity and without decline in quality of life (Stupp R., et al., JAMA 2015).

Applying TTFields at 150 kHz to the brain for the treatment of 1-5 brain metastasis from NSCLC using the NovoTTF-100M device has been demonstrated to be safe in a pilot study, where patients were randomized after local therapy of their brain metastasis by neurosurgery and/or stereotactic radiosurgery to receive either NovoTTF-100M treatment or supportive care alone. Eighteen (18) patients have been enrolled in the study. There have been no device-related serious adverse events (SAE) reported to date (Brozova H., et al., Neuro Oncol 2016).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with 1-10 brain metastases from NSCLC which are amenable to stereotactic radiosurgery (SRS). In addition, all patients must meet all eligibility criteria.

Eligible patients will be randomly assigned to one of two groups:

1. Patients undergo SRS followed by TTFields using the NovoTTF-200M System
2. Patients undergo SRS alone and receive supportive care. Patients in both arms of the study may receive systemic therapy for their NSCLC at the discretion of their treating physician.

Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients enrolled in both arms. If assigned to the NovoTTF-200M group, the patients will be treated continuously with the device until second intracranial progression.

On both arms, patients who recur anywhere in the brain will be offered one of the following salvage treatments (according to local practice) including, but not limited to:

• Surgery
• Repeat SRS
• Whole brain radiotherapy (WBRT) Patients on the control arm will be offered to cross over to the NovoTTF-200M arm of the study and receive TTFields with or without salvage therapy for second intracranial progression if the investigator believes it is in the best interest of the patient and patient agrees.

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 (150 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 electrically- charged cellular components of these cells to change their location within the dividing cell, disrupting their normal function and ultimately leading to cell death.. 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 interfere with the normal orientation of these tiny motors related to other cellular components since they are electrically-charged as well. As a result of these two effects, tumor cell division is slowed, results in cellular death or reverses 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. Finally, the frequency of TTFields applied to each type of cancer is specific and may not damage normally dividing cells in healthy tissues. In conclusion, TTFields hold the promise of serving as a brand new treatment for brain metastases from NSCLC with very few side effects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 270 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC).
• Study Start Date: July 2016
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: NovoTTF-200M device; NovoTTF-200M device Patients undergo SRS followed by continuous TTFields treatment using the NovoTTF-200M device. TTFields 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-200M device; Other: Best Standard of Care
Active Comparator: Best Standard of Care; Patients will undergo SRS alone and be treated with the best known standard of care for Non-Small Cell Lung Cancer metastatic to the brain.	Other: Best Standard of Care

Outcome Measures

Primary Outcome Measures :

1. Time to intracranial progression [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. Time to neurocognitive failure [ Time Frame: 3 years ]
   Measured by cognitive decline on a battery of tests: Hopkins Verbal Learning Test (HVLT-R) free recall, delayed recall, and delayed recognition; Controlled Oral Word Association Test (COWAT); and Trail Making Tests (TMT) Parts A and B
2. Overall survival [ Time Frame: 3 years ]
3. Radiological response in the brain following study treatments [ Time Frame: 3 years ]
4. Time to second intracranial progression [ Time Frame: 3 years ]
5. Time to intracranial progression, measured from the date of first SRS treatment to intracranial progression (per modified RECIST 1.1 Criteria) or neurological death, whichever occurs first. [ Time Frame: 3 years ]
6. Time to first and second intracranial progression evaluated in two cohorts of patients, 1-4 brain metastases and 5-10 brain metastases. [ Time Frame: 3 years ]
7. Rate of intracranial progression at 2, 4, 6, 8, 10, 12 months after first SRS treatment [ Time Frame: 3 years ]
8. Time to distant progression, as measured from the date of first SRS treatment to a new intracranial lesion [ Time Frame: 3 years ]
9. Rate of decline in cognitive function as measured by HVLT-R free recall, delayed recall and delayed recognition, COWAT and TMT Parts A and B at 2, 4, 6, 8, 10, 12 months follow-up. [ Time Frame: 3 years ]
10. Neurocognitive failure-free survival [ Time Frame: 3 years ]
    Defined from the date of first SRS treatment to neurocognitive failure (as measured by HVLT-R free recall, delayed recall, and delayed recognition; COWAT; and TMT Parts A and B) or death (whichever occurs first), censored at the last neurocognitive assessment on which the patient was reported alive without neurocognitive failure
11. Quality of Life using the EORTC QLQ C30 with BN20 addendum [ Time Frame: 3 years ]
12. Toxicity during NovoTTF-200M treatment based on incidence and severity of treatment emergent adverse events as evaluated using the CTCAE version 4.0 [ Time Frame: 3 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 18 years of age and older
2. Life expectancy of ≥ 3 months
3. New diagnosis of brain metastases from a histologically or cytologically confirmed primary or metastatic NSCLC tumor within 5 years of registration on the study. If the original histological proof of malignancy is greater than 5 years, then pathological confirmation is required (i.e.: from extra-cranial or intracranial disease).

5. 1 inoperable brain metastasis or 2- 10 brain lesions per screening MRI, confirmed by contrast enhanced MRI amenable to SRS according to the following criteria:

a. largest tumor volume < 10 cc b. longest tumor diameter < 3 cm c. Cumulative volume of all tumors ≤ 15 cc 6. At least one measurable disease per study protocol 7. Patients must be receiving optimal therapy for their extracranial disease according to local practice at each center. Patients may continue on systemic therapy while receiving TTFields.

8. Able to operate the NovoTTF-200M device independently or with the help of a caregiver 9. Clinical trials prior to enrollment are allowed, as long as no brain directed therapy was included (current treatment trials are exclusionary)

Exclusion Criteria:

1. Patients who are known to have somatic tumor mutations in the following genes, for which targeted agents are available that directly affect the treatment of brain metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ROS-1 proto- oncogene, and proto-oncogene B-RAF
2. Patients who have a single, operable brain metastasis
3. Patients with significant edema leading to risk of brain herniation
4. Patients with midline shift > 10mm
5. Patients with intractable seizures
6. Leptomeningeal metastases
7. Recurrent brain metastases
8. Prior WBRT for newly diagnosed brain metastases

9. Severe comorbidities:

   1. Clinically-significant inadequate hematological, hepatic and renal function, defined as: Neutrophil count < 1.5 x 10 9/L and platelet count < 100 x 10^9/L; bilirubin > 1.5 x upper limit of normal (ULN); aspartate transaminase (AST) and/or alanine aminotransferase (ALT) > 2.5 x ULN or > 5 x ULN if patient has documented liver metastases; and serum creatinine > 1.5 x ULN
   2. History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/ third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea).
   3. History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the study.
   4. History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable
   5. Active infection or serious underlying medical condition that would impair the ability of the patient to received protocol therapy
   6. 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
10. Implantable electronic medical devices in the brain
11. Known allergies to medical adhesives or hydrogel
12. Currently pregnant or breastfeeding
13. Planned concurrent brain directed therapy (beyond SRS and NovoTTF-200M as per protocol)

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Comprehensive Cancer Center

Birmingham, Alabama, United States, 35233

Grandview Medical Center - Cancer Center

Birmingham, Alabama, United States, 35243-3326

Infirmary Cancer Care

Mobile, Alabama, United States, 36607

United States, Arizona

Barrow Neurological Institute

Phoenix, Arizona, United States, 85013-4407

Mayo Clinic Phoenix

Phoenix, Arizona, United States, 85054

United States, California

MemorialCare Cancer Institute

Long Beach, California, United States, 90806

The Center for Cancer Prevention and Treatment at St. Joseph Hospital of Orange

Orange, California, United States, 92868

Kaiser Permanente Redwood City

Redwood City, California, United States, 94063

Dignity Health - Mercy Cancer Centers

Sacramento, California, United States, 95816

Kaiser Permanente - Sacramento

Sacramento, California, United States, 95825

Sharp HealthCare

San Diego, California, United States, 92123

University of California

San Francisco, California, United States, 94117

United States, Colorado

St. Mary's Medical Center - Grand Junction

Grand Junction, Colorado, United States, 81501

Banner North Colorado Medical Center (NCMC) - Oncology - Greeley

Greeley, Colorado, United States, 80631

Banner MD Anderson Cancer Center - McKee Medical Center

Loveland, Colorado, United States, 805838

United States, Florida

Baptist MD Anderson Cancer Center

Jacksonville, Florida, United States, 32207

UF Health Jacksonville

Jacksonville, Florida, United States, 32209

Mayo Clinic

Jacksonville, Florida, United States, 32224

Miami Cancer Institute

Miami, Florida, United States, 33176

Adult Oncology Research

Orlando, Florida, United States, 32806

UF Health Cancer Center

Orlando, Florida, United States, 32806

BRCR Medical Center INC

Plantation, Florida, United States, 33324

United States, Georgia

Piedmont Brain Tumor Center

Atlanta, Georgia, United States, 30309

Memorial Health University Medical Center

Savannah, Georgia, United States, 31404-6220

United States, Illinois

CDH-Delnor Health System

Warrenville, Illinois, United States, 60555

United States, Kansas

University of Kansas Cancer Center and Medical Pavilion

Kansas City, Kansas, United States, 66160

United States, Kentucky

University of Kentucky HealthCare

Lexington, Kentucky, United States, 40536

University of Louisville-James Graham Brown Cancer Center

Louisville, Kentucky, United States, 40202-5700

United States, Louisiana

Ochsner Health System

New Orleans, Louisiana, United States, 70121

Willis-Knighton Cancer Center

Shreveport, Louisiana, United States, 71103

United States, Maryland

University of Maryland

Baltimore, Maryland, United States, 21201

Walter Reed National Military Medical Center

Bethesda, Maryland, United States, 20814

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Minnesota

Abbott Northwestern Hospital - Givens Brain Tumor Center

Minneapolis, Minnesota, United States, 55407

John Nasseff Neuroscience Institute ANW Brain Tumor Center

Minneapolis, Minnesota, United States, 55407

University of Minnesota Medical Center (UMMC) - Fairview - Masonic Cancer Clinic

Minneapolis, Minnesota, United States, 55455-0341

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Missouri

Ellis Fischel Cancer Center, University of Missouri Healthcare

Columbia, Missouri, United States, 65212

Oncology Research | Mercy Research

Saint Louis, Missouri, United States, 63141

United States, Nevada

Renown Regional Medical Center

Reno, Nevada, United States, 89502

United States, New Jersey

MD Anderson Cancer Center at Cooper

Camden, New Jersey, United States, 08103

United States, North Carolina

UNC - Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States, 27599

Vidant Medical Center

Greenville, North Carolina, United States, 27834

Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer Center

Winston-Salem, North Carolina, United States, 27157-0001

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Oregon

Providence St. Vincent Medical Center

Portland, Oregon, United States, 97225

United States, Pennsylvania

Geisinger Medical Center

Danville, Pennsylvania, United States, 17822

United States, Rhode Island

Rhode Island Hospital

Providence, Rhode Island, United States, 02903

United States, South Carolina

Medical University of South Carolina- Hollings Cancer Center

Charleston, South Carolina, United States, 29425-8900

Prisma Health - Upstate

Greenville, South Carolina, United States, 29605

United States, Tennessee

Erlanger Baroness Hospital

Chattanooga, Tennessee, United States, 37403

West Cancer Center

Germantown, Tennessee, United States, 38138

United States, Texas

Mischer Neuroscience Associates - Texas Medical Center

Houston, Texas, United States, 77030-1536

Houston Methodist Hospital

Houston, Texas, United States, 77030

Texas Oncology

McKinney, Texas, United States, 75701

Texas Oncology

Plano, Texas, United States, 75093

Baylor Scott & White Medical Center - Temple

Waco, Texas, United States, 76712-8897

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

United States, Wisconsin

Aurora Research Institute

Milwaukee, Wisconsin, United States, 53215-5221

Austria

Medizinische Universität Innsbruck

Innsbruck, Austria, 6020

Bulgaria

UMHAT Sv. Ivan Rilski EAD, Department of Medical Oncology

Sofia, Bulgaria, 1431

University Multiprofile Hospital for Active Treatment Sofiamed, Department of Medical Oncology

Sofia, Bulgaria, 1797

Canada, Manitoba

Cancercare Manitoba

Winnipeg, Manitoba, Canada, R3E 0V9

Canada, Quebec

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada, H2L 4M1

Jewish General Hospital

Montreal, Quebec, Canada, H3T 1E2

Le CIUSSS de I'Est-de-L'ile de Montreal - Hôpital Maisonneuve Rosemont

Montréal, Quebec, Canada, H1T-2M4

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

Sherbrooke, Quebec, Canada, J1H 5N4

China, Chaoyang

Cancer Hospital Chinese Academy of Medical Sciences

Beijing, Chaoyang, China, 100023

China, Guangdong

The First Affiliated Hospital of Guangdong Pharmaceutical University

Guangzhou, Guangdong, China

China, Hubei

Hubei Cancer Hospital

Wuhan, Hubei, China

Zhongnan Hospital of Wuhan University

Wuhan, Hubei, China

China, Jiangsu

Nanjing Drum Tower Hospital

Nanjing, Jiangsu, China, 210008

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

Northern Jiangsu People's Hospital

Yangzhou, Jiangsu, China, 225007

China, Liaoning

Liaoning Cancer Hospital

Shenyang, Liaoning, China, 110042

China, Shaanxi

First Affiliated Hospital of Xi'an Jiaotong University

Xi'an, Shaanxi, China, 710063

China, Shandong

Qilu Hospital of Shandong University

Jinan, Shandong, China

Shandong Cancer Hospital

Jinan, Shandong, China

Qingdao Central Hospital

Qingdao, Shandong, China

China, Sichuan

Zigong Fourth People's Hospital

Zigong, Sichuan, China

China, Tianjin

Tianjin Medical University Cancer Institute and Hospital

Tianjin, Tianjin, China, 300060

China, Xuhui District

Fudan University Shanghai Cancer Center

Shanghai, Xuhui District, China

China, Zhejiang

Taizhou Hospital, Zhejiang Province

Zhejiang, Zhejiang, China

China

Peking University Third Hospital

Beijing, China

The First Hospital of Jilin University

Changchun, China

The Second Affiliated Hospital Of Xingtai Medical College

Hebei, China

The First Hospital of China Medical University

Shenyang, China

The University of Hong Kong-Shenzhen Hospital

Shenzhen, China

The First Affiliated Hospital of Xiamen University

Xiamen, China

Croatia

Radiochirugia Zagreb

Sveta Nedelja, Croatia, 10431

France

University Hospital Lille

Lille, France, 59037

Clairval Hospital Center

Marseille, France, 13009

Hopital Pitié-Salpétriere

Paris, France, 75013

Centre Hospitalier Universitaire de Saint-Étienne

Saint-Étienne, France, 42055

Germany

Klinik für Radioonkologie und Strahlentherapie der Charité Universitätsmedizin Berlin Campus Charité Virchow-Klinikum

Berlin, Germany, 13353

Universitätsklinikum Düsseldorf

Düsseldorf, Germany, 40225

Dr. Senckenbergisches Institut for Neurooncology,

Frankfurt am Main, Germany, 60528

Dr. Senckenbergisches Institut für Neuroonkologie, Zentrum der Neurologie und Neurochirurgie

Frankfurt am main, Germany, 60528

Universitätsklinikum Halle (Saale), Klinik für Innere Medizin IV, Hämatologie / Onkologie

Halle (Saale), Germany, 06120

Heidelberg University Clinic for Radiooncology and Radiation Therapy

Heidelberg, Germany, 69120

Hong Kong

Queen Mary Hospital

Hong Kong, Hong Kong

Hungary

National Koranyi Institute of Tb and Pulmonology

Budapest, Hungary, 1122

Onkologiai Osztaly, Balassa Janos Korhaz

Szekszárd, Hungary

Geza Hetenyi Hospital-Clinic of Jasz-Nagykun-Szolnok County

Szolnok, Hungary, 5000

Israel

Rambam Medical Center

Haifa, Israel, 3109601

Hadassah Medical Organization

Jerusalem, Israel, 91120

Rabin Medical Center

Petah Tikva, Israel, 4941492

Sheba Medical Center

Ramat Gan, Israel

Sourasky Medical Center

Tel Aviv, Israel

Italy

A.O.S.G. Moscati Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità

Avellino, Italy, 83100

General Hospital Gavazzeni

Bergamo, Italy, 24125

Radioterapia Oncologica AOU Careggi

Firenze, Italy, 50134

Azienda Socio Sanitaria Territoriale di Lecco

Lecco, Italy

University Hospital of Messina AOU Policlinico "G. Martino"

Messina, Italy, 98125

The IRCCS Carlo Besta Neurological Institute Foundation

Milan, Italy, 20133

A.O.U Città della Salute e della Scienza di Torino

Torino, Italy, 10126

Poland

Marek Harat Private Practice, Neurosurgery and Radiation Oncology

Bydgoszcz, Poland, 85357

University Clinical Center

Gdańsk, Poland

Maria Sklodowska-Curie National Research Institute of Oncology

Gliwice, Poland, 44-101

MS Clinsearch Sp. z.o.o.

Lublin, Poland, 20-064

Szpital Kliniczny Przemienienia Pańskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu

Poznań, Poland

Gamma Knife Center Warsaw

Warsaw, Poland, 03-242

Serbia

Center for Neuro-oncology, Neurosurgery Clinic, Clinical Center of Serbia

Belgrad, Serbia, 11000

Spain

Catalan Institute of Oncology

Barcelona, Spain

Hospital Universitario HM Sanchinarro Edificio CIOCC

Madrid, Spain, 28050

Clinica Universidad de Navarra

Pamplona, Spain

Sponsors and Collaborators

NovoCure GmbH

Investigators

• Principal Investigator: Minesh Mehta, MD; Miami Cancer Institute, Miami FL USA
• Principal Investigator: Paul Brown, MD; MD Anderson Cancer Center, Houston TX USA
• Principal Investigator: Vinai Gondi, MD; Northwestern Medicine Cancer Center, Warenville IL USA
• Principal Investigator: Manmeet Ahluwalia, MD; Cleveland Clinic, Cleveland OH USA

More Information

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.

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.

Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. doi: 10.1016/j.ejca.2012.04.011. Epub 2012 May 18.

Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015 Dec 11;5:18046. doi: 10.1038/srep18046.

Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol. 2014 Oct;41 Suppl 6:S35-41. doi: 10.1053/j.seminoncol.2014.09.006. Epub 2014 Sep 8.

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.

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.

Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013 Sep;81(3):445-450. doi: 10.1016/j.lungcan.2013.06.025. Epub 2013 Jul 23.

Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, Suh JH, van den Bent MJ, Vogelbaum MA, Wen PY; Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015 Jun;16(6):e270-8. doi: 10.1016/S1470-2045(15)70057-4. Epub 2015 May 27.

Brozova H, Lucas A, Salmaggi A, Vymazal J. COMET: A phase II randomized study of TTFields versus supportive care in non-small cell lung cancer patients with 1-5 brain metastases - initial safety results. Neuro Oncol. 2015 Nov; 17 (suppl 5): v46. doi:10.1093/neuonc/nov208.6

• Responsible Party: NovoCure GmbH
• ClinicalTrials.gov Identifier: NCT02831959
• Other Study ID Numbers: EF-25 METIS
• First Posted: July 13, 2016
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by NovoCure Ltd. ( NovoCure GmbH ):

Non-Small Cell Lung Cancer; NSCLC; Brain metastases; Treatment; Minimal toxicity; TTFields; TTF; Tumor Treating Fields; Novocure; SRS; Stereotactic radiosurgery

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Brain Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplastic Processes; Pathologic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases