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).

Brain Metastases From Non-small Cell Lung Cancer (NSCLC) Clinical Trial

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).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02831959
• Other study ID #: EF-25 METIS
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 2016
• Est. completion date: December 2024

Study information

• Verified date: March 2023
• Source: NovoCure Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 270
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Brain Metastases From Non-small Cell Lung Cancer (NSCLC)
• Brain Neoplasms
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Neoplasm Metastasis

Intervention

Device:
• NovoTTF-200M device

Other:
• Best Standard of Care

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Bulgaria	UMHAT Sv. Ivan Rilski EAD, Department of Medical Oncology	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment Sofiamed, Department of Medical Oncology	Sofia
Canada	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Le CIUSSS de I'Est-de-L'ile de Montreal - Hôpital Maisonneuve Rosemont	Montréal	Quebec
Canada	(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie	Sherbrooke	Quebec
Canada	Cancercare Manitoba	Winnipeg	Manitoba
China	Cancer Hospital Chinese Academy of Medical Sciences	Beijing	Chaoyang
China	Peking University Third Hospital	Beijing
China	The First Hospital of Jilin University	Changchun
China	The First Affiliated Hospital of Guangdong Pharmaceutical University	Guangzhou	Guangdong
China	The Second Affiliated Hospital Of Xingtai Medical College	Hebei
China	Qilu Hospital of Shandong University	Jinan	Shandong
China	Shandong Cancer Hospital	Jinan	Shandong
China	Nanjing Drum Tower Hospital	Nanjing	Jiangsu
China	Qingdao Central Hospital	Qingdao	Shandong
China	Fudan University Shanghai Cancer Center	Shanghai	Xuhui District
China	Liaoning Cancer Hospital	Shenyang	Liaoning
China	The First Hospital of China Medical University	Shenyang
China	The University of Hong Kong-Shenzhen Hospital	Shenzhen
China	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu
China	Tianjin Medical University Cancer Institute and Hospital	Tianjin	Tianjin
China	Hubei Cancer Hospital	Wuhan	Hubei
China	Zhongnan Hospital of Wuhan University	Wuhan	Hubei
China	First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi
China	The First Affiliated Hospital of Xiamen University	Xiamen
China	Northern Jiangsu People's Hospital	Yangzhou	Jiangsu
China	Taizhou Hospital, Zhejiang Province	Zhejiang	Zhejiang
China	Zigong Fourth People's Hospital	Zigong	Sichuan
Croatia	Radiochirugia Zagreb	Sveta Nedelja
France	University Hospital Lille	Lille
France	Clairval Hospital Center	Marseille
France	Hopital Pitié-Salpétriere	Paris
France	Centre Hospitalier Universitaire de Saint-Étienne	Saint-Étienne
Germany	Klinik für Radioonkologie und Strahlentherapie der Charité Universitätsmedizin Berlin Campus Charité Virchow-Klinikum	Berlin
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Dr. Senckenbergisches Institut for Neurooncology,	Frankfurt am Main
Germany	Dr. Senckenbergisches Institut für Neuroonkologie, Zentrum der Neurologie und Neurochirurgie	Frankfurt am main
Germany	Universitätsklinikum Halle (Saale), Klinik für Innere Medizin IV, Hämatologie / Onkologie	Halle (Saale)
Germany	Heidelberg University Clinic for Radiooncology and Radiation Therapy	Heidelberg
Hong Kong	Queen Mary Hospital	Hong Kong
Hungary	National Koranyi Institute of Tb and Pulmonology	Budapest
Hungary	Onkologiai Osztaly, Balassa Janos Korhaz	Szekszárd
Hungary	Geza Hetenyi Hospital-Clinic of Jasz-Nagykun-Szolnok County	Szolnok
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Medical Organization	Jerusalem
Israel	Rabin Medical Center	Petah Tikva
Israel	Sheba Medical Center	Ramat Gan
Israel	Sourasky Medical Center	Tel Aviv
Italy	A.O.S.G. Moscati Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità	Avellino
Italy	General Hospital Gavazzeni	Bergamo
Italy	Radioterapia Oncologica AOU Careggi	Firenze
Italy	Azienda Socio Sanitaria Territoriale di Lecco	Lecco
Italy	University Hospital of Messina AOU Policlinico "G. Martino"	Messina
Italy	The IRCCS Carlo Besta Neurological Institute Foundation	Milan
Italy	A.O.U Città della Salute e della Scienza di Torino	Torino
Poland	Marek Harat Private Practice, Neurosurgery and Radiation Oncology	Bydgoszcz
Poland	University Clinical Center	Gdansk
Poland	Maria Sklodowska-Curie National Research Institute of Oncology	Gliwice
Poland	MS Clinsearch Sp. z.o.o.	Lublin
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan
Poland	Gamma Knife Center Warsaw	Warsaw
Serbia	Center for Neuro-oncology, Neurosurgery Clinic, Clinical Center of Serbia	Belgrad
Spain	Catalan Institute of Oncology	Barcelona
Spain	Hospital Universitario HM Sanchinarro Edificio CIOCC	Madrid
Spain	Clinica Universidad de Navarra	Pamplona
United States	Piedmont Brain Tumor Center	Atlanta	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Grandview Medical Center - Cancer Center	Birmingham	Alabama
United States	University of Alabama at Birmingham Comprehensive Cancer Center	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	MD Anderson Cancer Center at Cooper	Camden	New Jersey
United States	UNC - Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina- Hollings Cancer Center	Charleston	South Carolina
United States	Erlanger Baroness Hospital	Chattanooga	Tennessee
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ellis Fischel Cancer Center, University of Missouri Healthcare	Columbia	Missouri
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	West Cancer Center	Germantown	Tennessee
United States	St. Mary's Medical Center - Grand Junction	Grand Junction	Colorado
United States	Banner North Colorado Medical Center (NCMC) - Oncology - Greeley	Greeley	Colorado
United States	Prisma Health - Upstate	Greenville	South Carolina
United States	Vidant Medical Center	Greenville	North Carolina
United States	Houston Methodist Hospital	Houston	Texas
United States	Mischer Neuroscience Associates - Texas Medical Center	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Mayo Clinic	Jacksonville	Florida
United States	UF Health Jacksonville	Jacksonville	Florida
United States	University of Kansas Cancer Center and Medical Pavilion	Kansas City	Kansas
United States	University of Kentucky HealthCare	Lexington	Kentucky
United States	MemorialCare Cancer Institute	Long Beach	California
United States	University of Louisville-James Graham Brown Cancer Center	Louisville	Kentucky
United States	Banner MD Anderson Cancer Center - McKee Medical Center	Loveland	Colorado
United States	Texas Oncology	McKinney	Texas
United States	Miami Cancer Institute	Miami	Florida
United States	Aurora Research Institute	Milwaukee	Wisconsin
United States	Abbott Northwestern Hospital - Givens Brain Tumor Center	Minneapolis	Minnesota
United States	John Nasseff Neuroscience Institute ANW Brain Tumor Center	Minneapolis	Minnesota
United States	University of Minnesota Medical Center (UMMC) - Fairview - Masonic Cancer Clinic	Minneapolis	Minnesota
United States	Infirmary Cancer Care	Mobile	Alabama
United States	Ochsner Health System	New Orleans	Louisiana
United States	The Center for Cancer Prevention and Treatment at St. Joseph Hospital of Orange	Orange	California
United States	Adult Oncology Research	Orlando	Florida
United States	UF Health Cancer Center	Orlando	Florida
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Mayo Clinic Phoenix	Phoenix	Arizona
United States	Texas Oncology	Plano	Texas
United States	BRCR Medical Center INC	Plantation	Florida
United States	Providence St. Vincent Medical Center	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Kaiser Permanente Redwood City	Redwood City	California
United States	Renown Regional Medical Center	Reno	Nevada
United States	Dignity Health - Mercy Cancer Centers	Sacramento	California
United States	Kaiser Permanente - Sacramento	Sacramento	California
United States	Oncology Research | Mercy Research	Saint Louis	Missouri
United States	Sharp HealthCare	San Diego	California
United States	University of California	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	University of Washington Medical Center	Seattle	Washington
United States	Willis-Knighton Cancer Center	Shreveport	Louisiana
United States	Baylor Scott & White Medical Center - Temple	Waco	Texas
United States	CDH-Delnor Health System	Warrenville	Illinois
United States	Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
NovoCure GmbH

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Canada,  China,  Croatia,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Italy,  Poland,  Serbia,  Spain, 

References & Publications (10)

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

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. — View 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. — View 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. — View 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. — View 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. — View Citation

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to intracranial progression		3 years
Secondary	Time to neurocognitive failure	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	3 years
Secondary	Overall survival		3 years
Secondary	Radiological response in the brain following study treatments		3 years
Secondary	Time to second intracranial progression		3 years
Secondary	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
Secondary	Time to first and second intracranial progression evaluated in two cohorts of patients, 1-4 brain metastases and 5-10 brain metastases.		3 years
Secondary	Rate of intracranial progression at 2, 4, 6, 8, 10, 12 months after first SRS treatment		3 years
Secondary	Time to distant progression, as measured from the date of first SRS treatment to a new intracranial lesion		3 years
Secondary	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
Secondary	Neurocognitive failure-free survival	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	3 years
Secondary	Quality of Life using the EORTC QLQ C30 with BN20 addendum		3 years
Secondary	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