Clinical trial NCT02973789: Effect of Tumor Treating Fields (TTFields) (150 kHz) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure (LUNAR)
Official title: LUNAR: Pivotal, Randomized, Open-label Study of Tumor Treating Fields (TTFields) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nonsmall Cell Lung Cancer
NSCLC
Keywords: Non-Small Cell Lung Cancer
NSCLC
Treatment
Minimal Toxicity
TTFields
TTF
Tumor Treating Fields
Novocure
Docetaxel
PD-1 inhibitor
PD-L1 inhibitor
Immune checkpoint inhibitor
Lead sponsor: NovoCure Ltd.
Sponsor class: INDUSTRY
First posted: 2016-11-25
Enrollment: 276
Sex: ALL
Minimum age (years): 22
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of TTFields, using the NovoTTF-200T device, concurrent with standard therapies for stage 4 NSCLC patients, following progression while on or after platinum based treatment. 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 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 and PD-1 inhibitors. TTFields have been demonstrated to act synergistically with taxanes and have been shown to be additive when combined with PD-1 inhibitors. In addition, TTFields have shown to inhibit metastatic spread of malignant melanoma in in vivo experiment.

In a pilot study, 42 patients with advanced NSCLC who had 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). The combination was well tolerated and the only device-related adverse event was mild to moderate contact dermatitis. 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).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with squamous or non-squamous, stage 4 NSCLC who had disease progression on or after receiving platinum based chemotherapy. In addition, all patients must meet all eligibility criteria.

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

Patients receive docetaxel or immune checkpoint inhibitor in combination with TTFields using the NovoTTF-100L System.

Patients receive docetaxel or immune checkpoint inhibitor without TTFields. 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-100L group, the patients will be treated continuously with the device until disease progression in the thorax and/or liver according to RECIST or irRECIST (Immune-Related Response Evaluation Criteria In Solid Tumors) (depending if the patient is receiving docetaxel or immune checkpoint inhibitor, respectively).

On both arms, patients who have disease progression according to RECIST or irRECIST (depending if the patient is receiving docetaxel or immune checkpoint inhibitor, respectively) will switch to a third line treatment according to local practice.

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 NSCLC with very few side effects.

Eligibility criteria: Inclusion Criteria:

1. 22 years of age and older (some regional variations to inclusion age exist)
2. Life expectancy of ≥ 3 months
3. Histological diagnosis of squamous or non-squamous, inoperable, metastatic NSCLC
4. Diagnosis of radiological progression while on or after first platinum-based systemic therapy administered for advanced or metastatic disease.

   1. Patients who received adjuvant or neoadjuvant platinum-based chemotherapy (after surgery and/or radiation therapy) and developed metastatic disease within 6 months of completing therapy are eligible.
   2. Patients with metastatic disease more than 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum- based regimen given to treat the advanced or metastatic disease, are eligible.
   3. Patients should not receive any systemic therapy after platinum failure before enrollment into the study. Maintenance therapy after platinum based therapy and prior to progression is allowed.
5. ECOG Score of 0-2
6. Assigned by the physician to receive either docetaxel or immune checkpoint inhibitor per standard of care regimen
7. Able to operate the NovoTTF-200T device independently or with the help of a caregiver
8. Signed informed consent for the study protocol

Exclusion Criteria:

1. Metastases to central nervous system (CNS) with clinical symptoms or evidence of new metastases to CNS during screening. Patients who previously received treatments for the metastases to CNS, are stable and meet the following requirements are allowed to be enrolled:

   1. The patients are neurologically returned to baseline (except for residual signs or symptoms related to CNS treatment).
   2. No treatment for the metastases to CNS during the screening period (e.g. surgery, radiotherapy, corticosteroid therapy- prednisone \> 10 mg/day or equivalent).
   3. No progress in CNS lesions as indicated by MRI within 14 days prior to randomization.
   4. No meningeal metastasis or spinal cord compression.
2. Patients planned to receive immune checkpoint inhibitor with contra-indications to receive immunotherapy
3. Patients planned to receive docetaxel with contra-indications to receive docetaxel
4. Severe comorbidities:

   1. Clinically significant (as determined by the investigator) hematological, hepatic and renal dysfunction, defined as: Neutrophil count \< 1.5 x 10\^9/L and platelet count \< 100 x 10\^9/L; bilirubin \> 1.5 x ULN; AST and/or 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 trial
   4. History of pericarditis
   5. History of interstitial lung disease
   6. History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable
   7. Active infection or serious underlying medical condition that would impair the ability of the patient to received protocol therapy
   8. 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
   9. Any other malignancy requiring anti-tumor treatment in the past three years, excluding treated stage I prostate cancer, in situ cervical cancer, in situ breast cancer and non-melanomatous skin cancer
5. Concurrent treatment with other experimental treatments for NSCLC while on the study
6. Implantable electronic medical devices (e.g. pacemaker, defibrillator) in the upper torso
7. Known allergies to medical adhesives or hydrogel
8. Pregnancy or breast-feeding (patients with reproductive potential must use effective contraception methods throughout the entire study period, as determined by their investigator/gynecologist)
9. Admitted to an institution by administrative or court order

Primary outcomes:
measure: Overall survival of patients treated with TTFields + docetaxel or immune checkpoint inhibitors vs. docetaxel or immune checkpoint inhibitors alone (superiority analysis)
timeFrame: 4 years
Secondary outcomes:
measure: Overall survival of patients treated with TTFields + docetaxel vs. docetaxel alone (superiority analysis)
timeFrame: 4 years
measure: Overall survival of patients treated with TTFields + immune checkpoint inhibitors vs. immune checkpoint inhibitors alone (superiority)
timeFrame: 4 years
measure: Overall Survival of patients treated with TTFields + docetaxel Vs. immune checkpoint inhibitors alone (non-inferiority analysis)
timeFrame: 4 years
measure: Progression-free survival of patients treated with docetaxel or immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone, based on RECIST Criteria
timeFrame: 4 years
measure: Overall radiological response rate (based on RECIST criteria) of patients treated with docetaxel or Immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone.
timeFrame: 4 years
measure: Quality of life using the EORTC QLQ C30 questionnaire with LC13 addendum
timeFrame: 4 years
measure: Analyses of the effects of NovoTTF-200T with each type of immune checkpoint inhibitor on overall survival and progression free survival
timeFrame: 4 years
measure: Analysis of the effects of NovoTTF-200T on overall survival and progression free survival within each histological subgroup (squamous and non-squamous)
timeFrame: 4 years
measure: The effect of treatment compliance with NovoTTF-200T on overall survival and progression free survival outcomes
timeFrame: 4 years
measure: Adverse events, severity and frequency based on Common Terminology Criteria for Adverse Events (CTCAE) V4.03
timeFrame: 4 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Alabama Research
state: Alabama
city: Chandler
country: United States
facility: Ironwood Cancer & Research Center
state: Arizona
city: Phoenix
country: United States
facility: Cancer Center at St. Joseph Hospital and Medical Center
state: Arizona
city: Beverly Hills
country: United States
facility: Beverly Hills Cancer Center
state: California
city: Fresno
country: United States
facility: California Cancer Associates for Research and Excellence, Inc. cCARE
state: California
city: Fullerton
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Laguna Hills
country: United States
facility: Saddleback Memorial Medical Center
state: California
city: Redlands
country: United States
facility: Redlands Community Hospital (Emad Ibrahim, MD, Inc.)
state: California
city: Sacramento
country: United States
facility: Dignity Health - Mercy Cancer Centers
state: California
city: Sacramento
country: United States
facility: Sutter Institute for Medical Research
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Greeley
country: United States
facility: Banner MD Anderson Cancer Center at North Colorado Medical Center
state: Colorado
city: Fairfield
country: United States
facility: Associated Neurologists of Southern CT, P.C.
state: Connecticut
city: Washington
country: United States
facility: Washington Cancer Institute at MedStar Washington Hospital Center
state: District of Columbia
city: Jacksonville
country: United States
facility: GenesisCare USA
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Orlando
country: United States
facility: Adult Oncology Research
state: Florida
city: Plantation
country: United States
facility: BRCR Medical Center INC
state: Florida
city: Chicago
country: United States
facility: University of Illinois Cancer Center
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare, P.C.
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University, School of Medicine, Simmons Cancer Institute at SIU
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Louisville
country: United States
facility: University Medical Center, Inc; DBA University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: LSU Health Sciences Center -New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Cancer Center
state: Louisiana
city: Shreveport
country: United States
facility: CHRISTUS Health
state: Louisiana
city: Lewiston
country: United States
facility: Central Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center, Division of Hematology and Oncology
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Farmington Hills
country: United States
facility: Clinical Oncology Associates
state: Michigan
city: Farmington Hills
country: United States
facility: Detroit Clinical Research Center
state: Michigan
city: Ypsilanti
country: United States
facility: Saint Joseph Mercy Health System
state: Michigan
city: Saint Paul
country: United States
facility: HealthPartners Institute, Regions Cancer Care Center
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: CHI Health Research Center
state: Nebraska
city: Omaha
country: United States
facility: Oncology Hematology West, PC dba Nebraska Cancer Specialists
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: OptumCare Cancer Care
state: Nevada
city: Reno
country: United States
facility: Renown Regional Medical Center Institute for Cancer
state: Nevada
city: Albuquerque
country: United States
facility: Presbyterian Cancer Center
state: New Mexico
city: Flushing
country: United States
facility: New York-Presbyterian/Queens Radiation Oncology
state: New York
city: Mount Kisco
country: United States
facility: Northern Westchester Hospital
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Cancer Center
state: New York
city: Charlotte
country: United States
facility: Oncology Specialists of Charlotte
state: North Carolina
city: Salisbury
country: United States
facility: W.G. Bill Hefner VA Med Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Piedmont Radiation Oncology, PA
state: North Carolina
city: Akron
country: United States
facility: Summa Health
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Bethlehem
country: United States
facility: Vita Medical Associates, P.C.
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Cancer Institute
state: Pennsylvania
city: Chattanooga
country: United States
facility: UT/Erlanger Oncology & Hematology
state: Tennessee
city: Amarillo
country: United States
facility: Texas Oncology - Amarillo
state: Texas
city: Arlington
country: United States
facility: Texas Oncology - Arlington
state: Texas
city: Corpus Christi
country: United States
facility: Christus Health Spohn Ministry
state: Texas
city: Dallas
country: United States
facility: Dallas VA Medical Center
state: Texas
city: Dallas
country: United States
facility: Texas Oncology- Baylor Charles A. Sammons Cancer Center
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Oncology Consultants, P.A.
state: Texas
city: McKinney
country: United States
facility: Texas Oncology-McKinney
state: Texas
city: Paris
country: United States
facility: Texas Oncology - Paris
state: Texas
city: Plano
country: United States
facility: Texas Oncology- Plano West
state: Texas
city: Waco
country: United States
facility: Baylor Scott & White Health/McClinton Cancer Center
state: Texas
city: Waco
country: United States
facility: Texas Oncology-Waco
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Bellevue
country: United States
facility: Overlake Medical Center & Clinics
state: Washington
city: Madison
country: United States
facility: UW Carbone Cancer Center
state: Wisconsin
city: Salzburg
country: Austria
facility: Medical University Salzburg, State Hospital, University hospital for internal medicine III / PMU
city: Brussels
country: Belgium
facility: Institut Jules Bordet - Department of Intensive Care and Thoracic Oncology
city: Herstal
country: Belgium
facility: Clinique André Renard Herstal Oncologie
city: Mechelen
country: Belgium
facility: AZ Sint Maarten
city: Plovdiv
country: Bulgaria
facility: Complex Oncology Center (COC) - Plovdiv EOOD,
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Universitaire de Sherbrooke (CIUSSS de l'Estrie - CHUS)
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Center
state: Saskatchewan
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Guangzhou
country: China
facility: Affiliated Cancer Hospital of Guangzhou Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
state: Henan
city: Zibo
country: China
facility: PKUCare Luzhong Hospital
state: Shandong
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Prague
country: Czechia
facility: General University Hospital in Prague
city: Prague
country: Czechia
facility: Thomayerova Nemocnice Dept. of Pneumology
city: Vitkovice
country: Czechia
facility: Vitkovicka nemocnice
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Bordeaux
country: France
facility: INSTITUT BERGONIE Centre Régional de Lutte Contre le Cancer
city: Lorient
country: France
facility: Groupe Hospitalier Bretagne Sud
city: Nîmes
country: France
facility: CHU Caremeau Service de Pneumologie
city: Paris
country: France
facility: AH-HP Hôpital Saint Louis
city: Saint-Quentin
country: France
facility: Centre Hospitalier de Saint-Quentin Service de pneumologie
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle - Universitätsklinik und Poliklinik für Innere Medizin IV
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Szekszárd
country: Hungary
facility: Tolna County, Balassa Janos Hospital, Department of oncology
city: Genova
country: Italy
facility: ASL 3, Ospedale Villa Scassi
city: Meldola
country: Italy
facility: IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
city: Ravenna
country: Italy
facility: UOC Oncologia Medica Presidio Ospedaliero di Ravenna AUSL della Romagna
city: Saronno
country: Italy
facility: Saronno Hospital
city: Harderwijk
country: Netherlands
facility: St Jansdal Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus Mc
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lublin
country: Poland
facility: MS Clinsearch Specjalistyczny NZOZ
city: Poznan
country: Poland
facility: Clinical Hospital of Przemienienia Pańskiego UM in Poznaniu
city: Szczecin
country: Poland
facility: Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie
city: Łódź
country: Poland
facility: Centrum Terapii Współczesnej
city: Belgrade
country: Serbia
facility: Bezanijska kosa Clinical Hospital Center
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova
state: Catalonia
city: Barcelona
country: Spain
facility: Hospital Quirón Teknon, Instituto Oncológico Dr. Rosell
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya Medical Oncology Department
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Universitari i Politécnic La Fe
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur Tumorzentrum Winterthur
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Voloshin T, Kaynan N, Davidi S, Porat Y, Shteingauz A, Schneiderman RS, Zeevi E, Munster M, Blat R, Tempel Brami C, Cahal S, Itzhaki A, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020 Jul;69(7):1191-1204. doi: 10.1007/s00262-020-02534-7. Epub 2020 Mar 6.