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).
- Conditions
- Brain Metastases From Non-small Cell Lung Cancer (NSCLC)
- Interventions
- Device: NovoTTF-200M deviceOther: Best Standard of Care
- Registration Number
- NCT02831959
- Lead Sponsor
- NovoCure GmbH
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 270
-
18 years of age and older
-
Life expectancy of ≥ 3 months
-
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).
-
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.
- 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)
-
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
-
Patients who have a single, operable brain metastasis
-
Patients with significant edema leading to risk of brain herniation
-
Patients with midline shift > 10mm
-
Patients with intractable seizures
-
Leptomeningeal metastases
-
Recurrent brain metastases
-
Prior WBRT for newly diagnosed brain metastases
-
Severe comorbidities:
- 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
- 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).
- 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.
- History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable
- Active infection or serious underlying medical condition that would impair the ability of the patient to received protocol therapy
- 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
-
Implantable electronic medical devices in the brain
-
Known allergies to medical adhesives or hydrogel
-
Currently pregnant or breastfeeding
-
Planned concurrent brain directed therapy (beyond SRS and NovoTTF-200M as per protocol)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description NovoTTF-200M device Best Standard of Care 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. NovoTTF-200M device 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. Best Standard of Care 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.
- Primary Outcome Measures
Name Time Method Time to intracranial progression 3 years
- Secondary Outcome Measures
Name Time Method Radiological response in the brain following study treatments 3 years Time to second intracranial progression 3 years 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. 3 years 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. 3 years Time to neurocognitive failure 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
Overall survival 3 years Time to first and second intracranial progression evaluated in two cohorts of patients, 1-4 brain metastases and 5-10 brain metastases. 3 years Rate of intracranial progression at 2, 4, 6, 8, 10, 12 months after first SRS treatment 3 years Time to distant progression, as measured from the date of first SRS treatment to a new intracranial lesion 3 years Neurocognitive failure-free survival 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
Quality of Life using the EORTC QLQ C30 with BN20 addendum 3 years Toxicity during NovoTTF-200M treatment based on incidence and severity of treatment emergent adverse events as evaluated using the CTCAE version 4.0 3 years
Trial Locations
- Locations (127)
Piedmont Brain Tumor Center
🇺🇸Atlanta, Georgia, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Fudan University Shanghai Cancer Center
🇨🇳Shanghai, Xuhui District, China
Peking University Third Hospital
🇨🇳Beijing, China
The First Affiliated Hospital of Xiamen University
🇨🇳Xiamen, China
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Abbott Northwestern Hospital - Givens Brain Tumor Center
🇺🇸Minneapolis, Minnesota, United States
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Willis-Knighton Cancer Center
🇺🇸Shreveport, Louisiana, United States
Ochsner Health System
🇺🇸New Orleans, Louisiana, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
Banner MD Anderson Cancer Center - McKee Medical Center
🇺🇸Loveland, Colorado, United States
The Center for Cancer Prevention and Treatment at St. Joseph Hospital of Orange
🇺🇸Orange, California, United States
Mayo Clinic Phoenix
🇺🇸Phoenix, Arizona, United States
University of Alabama at Birmingham Comprehensive Cancer Center
🇺🇸Birmingham, Alabama, United States
UF Health Jacksonville
🇺🇸Jacksonville, Florida, United States
St. Mary's Medical Center - Grand Junction
🇺🇸Grand Junction, Colorado, United States
BRCR Medical Center INC
🇺🇸Plantation, Florida, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Ellis Fischel Cancer Center, University of Missouri Healthcare
🇺🇸Columbia, Missouri, United States
Kaiser Permanente - Sacramento
🇺🇸Sacramento, California, United States
Banner North Colorado Medical Center (NCMC) - Oncology - Greeley
🇺🇸Greeley, Colorado, United States
University of California
🇺🇸San Francisco, California, United States
CDH-Delnor Health System
🇺🇸Warrenville, Illinois, United States
John Nasseff Neuroscience Institute ANW Brain Tumor Center
🇺🇸Minneapolis, Minnesota, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
UF Health Cancer Center
🇺🇸Orlando, Florida, United States
University of Kentucky HealthCare
🇺🇸Lexington, Kentucky, United States
University of Kansas Cancer Center and Medical Pavilion
🇺🇸Kansas City, Kansas, United States
Adult Oncology Research
🇺🇸Orlando, Florida, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
University of Louisville-James Graham Brown Cancer Center
🇺🇸Louisville, Kentucky, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Prisma Health - Upstate
🇺🇸Greenville, South Carolina, United States
Texas Oncology
🇺🇸Plano, Texas, United States
Vidant Medical Center
🇺🇸Greenville, North Carolina, United States
Mischer Neuroscience Associates - Texas Medical Center
🇺🇸Houston, Texas, United States
West Cancer Center
🇺🇸Germantown, Tennessee, United States
Erlanger Baroness Hospital
🇺🇸Chattanooga, Tennessee, United States
University Multiprofile Hospital for Active Treatment Sofiamed, Department of Medical Oncology
🇧🇬Sofia, Bulgaria
Aurora Research Institute
🇺🇸Milwaukee, Wisconsin, United States
UMHAT Sv. Ivan Rilski EAD, Department of Medical Oncology
🇧🇬Sofia, Bulgaria
Radiochirugia Zagreb
🇭🇷Sveta Nedelja, Croatia
Qingdao Central Hospital
🇨🇳Qingdao, Shandong, China
Zigong Fourth People's Hospital
🇨🇳Zigong, Sichuan, China
The Second Affiliated Hospital Of Xingtai Medical College
🇨🇳Hebei, China
The First Affiliated Hospital of Guangdong Pharmaceutical University
🇨🇳Guangzhou, Guangdong, China
University Hospital Lille
🇫🇷Lille, France
Onkologiai Osztaly, Balassa Janos Korhaz
🇭🇺Szekszárd, Hungary
Cancercare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Centre Hospitalier Universitaire de Saint-Étienne
🇫🇷Saint-Étienne, France
Geza Hetenyi Hospital-Clinic of Jasz-Nagykun-Szolnok County
🇭🇺Szolnok, Hungary
Maria Sklodowska-Curie National Research Institute of Oncology
🇵🇱Gliwice, Poland
The First Hospital of China Medical University
🇨🇳Shenyang, China
Universitätsklinikum Halle (Saale), Klinik für Innere Medizin IV, Hämatologie / Onkologie
🇩🇪Halle (Saale), Germany
Shandong Cancer Hospital
🇨🇳Jinan, Shandong, China
Hopital Pitié-Salpétriere
🇫🇷Paris, France
University Clinical Center
🇵🇱Gdańsk, Poland
A.O.S.G. Moscati Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità
🇮🇹Avellino, Italy
General Hospital Gavazzeni
🇮🇹Bergamo, Italy
Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Clairval Hospital Center
🇫🇷Marseille, France
Klinik für Radioonkologie und Strahlentherapie der Charité Universitätsmedizin Berlin Campus Charité Virchow-Klinikum
🇩🇪Berlin, Germany
Dr. Senckenbergisches Institut for Neurooncology,
🇩🇪Frankfurt am Main, Germany
Rambam Medical Center
🇮🇱Haifa, Israel
Hadassah Medical Organization
🇮🇱Jerusalem, Israel
The IRCCS Carlo Besta Neurological Institute Foundation
🇮🇹Milan, Italy
A.O.U Città della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Marek Harat Private Practice, Neurosurgery and Radiation Oncology
🇵🇱Bydgoszcz, Poland
Center for Neuro-oncology, Neurosurgery Clinic, Clinical Center of Serbia
🇷🇸Belgrad, Serbia
Radioterapia Oncologica AOU Careggi
🇮🇹Firenze, Italy
Catalan Institute of Oncology
🇪🇸Barcelona, Spain
Hospital Universitario HM Sanchinarro Edificio CIOCC
🇪🇸Madrid, Spain
Infirmary Cancer Care
🇺🇸Mobile, Alabama, United States
Grandview Medical Center - Cancer Center
🇺🇸Birmingham, Alabama, United States
Universitätsklinikum Düsseldorf
🇩🇪Düsseldorf, Germany
Dr. Senckenbergisches Institut für Neuroonkologie, Zentrum der Neurologie und Neurochirurgie
🇩🇪Frankfurt am main, Germany
Heidelberg University Clinic for Radiooncology and Radiation Therapy
🇩🇪Heidelberg, Germany
Kaiser Permanente Redwood City
🇺🇸Redwood City, California, United States
MemorialCare Cancer Institute
🇺🇸Long Beach, California, United States
Dignity Health - Mercy Cancer Centers
🇺🇸Sacramento, California, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
University of Minnesota Medical Center (UMMC) - Fairview - Masonic Cancer Clinic
🇺🇸Minneapolis, Minnesota, United States
MD Anderson Cancer Center at Cooper
🇺🇸Camden, New Jersey, United States
Oncology Research | Mercy Research
🇺🇸Saint Louis, Missouri, United States
Providence St. Vincent Medical Center
🇺🇸Portland, Oregon, United States
UNC - Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer Center
🇺🇸Winston-Salem, North Carolina, United States
Medical University of South Carolina- Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
Baylor Scott & White Medical Center - Temple
🇺🇸Waco, Texas, United States
Liaoning Cancer Hospital
🇨🇳Shenyang, Liaoning, China
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie
🇨🇦Sherbrooke, Quebec, Canada
Cancer Hospital Chinese Academy of Medical Sciences
🇨🇳Beijing, Chaoyang, China
Centre Hospitalier de l'Universite de Montreal (CHUM)
🇨🇦Montreal, Quebec, Canada
Zhongnan Hospital of Wuhan University
🇨🇳Wuhan, Hubei, China
The First Affiliated Hospital of Soochow University
🇨🇳Suzhou, Jiangsu, China
Le CIUSSS de I'Est-de-L'ile de Montreal - Hôpital Maisonneuve Rosemont
🇨🇦Montréal, Quebec, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Hubei Cancer Hospital
🇨🇳Wuhan, Hubei, China
Nanjing Drum Tower Hospital
🇨🇳Nanjing, Jiangsu, China
Qilu Hospital of Shandong University
🇨🇳Jinan, Shandong, China
Northern Jiangsu People's Hospital
🇨🇳Yangzhou, Jiangsu, China
Tianjin Medical University Cancer Institute and Hospital
🇨🇳Tianjin, Tianjin, China
First Affiliated Hospital of Xi'an Jiaotong University
🇨🇳Xi'an, Shaanxi, China
Taizhou Hospital, Zhejiang Province
🇨🇳Zhejiang, Zhejiang, China
The University of Hong Kong-Shenzhen Hospital
🇨🇳Shenzhen, China
The First Hospital of Jilin University
🇨🇳Changchun, China
National Koranyi Institute of Tb and Pulmonology
🇭🇺Budapest, Hungary
University Hospital of Messina AOU Policlinico "G. Martino"
🇮🇹Messina, Italy
Rabin Medical Center
🇮🇱Petah Tikva, Israel
Azienda Socio Sanitaria Territoriale di Lecco
🇮🇹Lecco, Italy
MS Clinsearch Sp. z.o.o.
🇵🇱Lublin, Poland
Gamma Knife Center Warsaw
🇵🇱Warsaw, Poland
Clinica Universidad de Navarra
🇪🇸Pamplona, Spain
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
Szpital Kliniczny Przemienienia Pańskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
🇵🇱Poznań, Poland
Sharp HealthCare
🇺🇸San Diego, California, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Medizinische Universität Innsbruck
🇦🇹Innsbruck, Austria
Queen Mary Hospital
🇭🇰Hong Kong, Hong Kong
Related News
NovoCure scoops FDA approval on wearable for metastatic cancer treatment
NovoCure scoops FDA approval on wearable for metastatic cancer treatment
NovoCure scoops FDA approval on wearable for metastatic cancer treatment - Yahoo
- Prev
- 1
- Next