Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme Clinical Trial

Official title:

A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients With Newly Diagnosed GBM.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00916409
• Other study ID #: EF-14
• Status: Completed
• Phase: Phase 3
• First received: June 5, 2009
• Last updated: April 7, 2017
• Start date: June 2009
• Est. completion date: March 2017

Study information

• Verified date: April 2017
• Source: NovoCure Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is a prospective, randomly controlled pivotal trial, designed to test the efficacy and safety of a medical device, the NovoTTF-100A, as an adjuvant to the best standard of care in the treatment of newly diagnosed GBM patients. 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 CLINICAL EXPERIENCE:

The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has been tested in a large prospective, randomized trial, in recurrent GBM. The outcome of subjects treated with the NovoTTF-100A device was compared to those treated with an effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A subjects had comparable overall survival to subjects receiving the best available chemotherapy in the US today. Similar results showing comparability of NovoTTF-100A to BSC chemotherapy were seen in all secondary endpoints.

Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer side effects in general, significantly fewer treatment related side effects, and significantly lower gastrointestinal, hematological and infectious adverse events compared to controls. The only device-related adverse events seen were a mild to moderate skin irritation beneath the device electrodes. Finally, quality of life measures were better in NovoTTF-100A subjects as a group when compared to subjects receiving effective best standard of care chemotherapy.

In a small scale pilot trial in newly diagnosed GBM patients, the treatment was well tolerated and suggested that NovoTTF-100A may improve time to disease progression and overall survival of newly diagnosed GBM patients. Although the number of patients in the pilot trial was small, The FDA has determined that the data gathered so far warrant testing of NovoTTF-100A treatment as a possible therapy for patients with newly diagnosed GBM.

DESCRIPTION OF THE TRIAL:

All patients included in this trial are newly diagnosed GBM patients who underwent a biopsy or surgery (with or without Gliadel wafers), followed by radiation therapy in combination with Temozolomide chemotherapy. In addition, all patients must meet all eligibility criteria.

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

1. Treatment with the NovoTTF-100A device in combination with Temozolomide chemotherapy.

2. Treatment with Temozolomide alone, as the best known standard of care.

Patients will be randomized at a 2:1 ratio (2 of every three patients who participate in the trial will be treated with the NovoTTF-100A device). Baseline tests will be performed in patients enrolled in both arms, including specific genetic tests done using tumor samples obtained during their initial surgery. If assigned to the NovoTTF-100A in combination with Temozolomide group, the patients will be treated continuously with the device until second progression. They will also receive temozolomide and possibly a second line treatment that can be one of the following: re-operation, local radiotherapy (gamma-knife), a second line of chemotherapy or a combination of the above.

NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. Electrode array placement will require shaving of the scalp before and frequently during the treatment. After an initial short visit to the clinic for training and monitoring, patients will be released to continue treatment at home where they can maintain their regular daily routine.

During the trial, regardless of which treatment group the patient was assigned to, he or she will need to return once every month to the clinic where an examination by a physician and a routine laboratory examinations will be done. These routine visits will continue for as long as the patient's disease is not progressing for the second time under the study treatment. If such occurs, patients will need to return once per month for two more months to the clinic for similar follow up examinations.

During the visits to the clinic patients will be examined physically and neurologically. Additionally, routine blood tests will be performed. A routine MRI of the head will be performed at baseline and every second month thereafter, until second progression. After this follow up plan, patients will be contacted once per month by telephone to answer basic questions about their health status.

SCIENTIFIC BACKGROUND:

Electric fields exert forces on electric charges similar to the way a magnet exerts forces on metallic particles within a magnetic field. These forces cause movement and rotation of electrically charged biological building blocks, much like the alignment of metallic particles seen along the lines of force radiating outwards from a magnet.

Electric fields can also cause muscles to twitch and if strong enough may heat tissues. TTFields are alternating electric fields of low intensity. This means that they change their direction repetitively many times a second. Since they change direction very rapidly (200 thousand times a second), they do not cause muscles to twitch, nor do they have any effects on other electrically activated tissues in the body (brain, nerves and heart). Since the intensities of TTFields in the body are very low, they do not cause heating.

The breakthrough finding made by NovoCure was that finely tuned alternating fields of very low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are multiplying, TTFields cause the building blocks of these cells to move and pile up in such a way that the cells physically explode. In addition, cancer cells also contain miniature building blocks which act as tiny motors in moving essential parts of the cells from place to place. TTFields cause these tiny motors to fall apart since they have a special type of electric charge.

As a result of these two effects, cancer tumor growth is slowed and can even reverse after continuous exposure to TTFields.

Other cells in the body (normal healthy tissues) are affected much less than cancer cells since they multiply at a much slower rate if at all. In addition TTFields can be directed to a certain part of the body, leaving sensitive areas out of their reach.

In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very few side effects and promising affectivity in slowing or reversing this disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 700
• Est. completion date: March 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Pathological evidence of GBM using WHO classification criteria.

2. > 18 years of age.

3. Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):

1. Patients may enroll in the study if received Gliadel wafers before entering the trial

2. Any additional treatments received prior to enrollment will be considered an exclusion.

3. Minimal dose for concomitant radiotherapy is 45 Gy

4. Karnofsky scale = 70

5. Life expectancy at least 3 months

6. Participants of childbearing age must use effective contraception.

7. All patients must sign written informed consent.

8. Treatment start date at least 4 weeks out from surgery.

9. Treatment start date at least 4 weeks out but not more than 7 weeks from the later of last dose of concomitant Temozolomide or radiotherapy.

Exclusion Criteria:

1. Progressive disease (according to MacDonald Criteria). If pseudoprogression is suspected, additional imaging studies must be performed to rule out true progression.

2. Actively participating in another clinical treatment trial

3. Pregnant

4. Significant co-morbidities at baseline which would prevent maintenance Temozolomide treatment:

1. Thrombocytopenia (platelet count < 100 x 103/µL)

2. Neutropenia (absolute neutrophil count < 1.5 x 103/µL)

3. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)

4. Significant liver function impairment - AST or ALT > 3 times the upper limit of normal

5. Total bilirubin > upper limit of normal

6. Significant renal impairment (serum creatinine > 1.7 mg/dL)

5. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.

6. Infra-tentorial tumor

7. Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness)

8. History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity to DTIC.

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme

Intervention

Device:
• NovoTTF-100A device
patients will be treated continuously with the NovoTTF-100A device, in addition to Temozolomide. NovoTTF-100A treatment will consist of wearing four electrically insulated electrode arrays on the head. The treatment enables the patient to maintain regular daily routine.

Drug:
• Temozolomide
maintenance Temozolomide will be administered according to the approved dosing scheme as follows: Maintenance Phase Cycle 1: Four weeks after completing the Temozolomide + Radiotherapy phase, Temozolomide is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. Cycles 2-6: At the start of Cycle 2, the dose is escalated to 200 mg/m2, if the CTC non-hematologic toxicity for Cycle 1 is Grade =2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is = 1.5 x 109/L, and the platelet count is = 100 x 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.

Locations

Country	Name	City	State
Austria	University Hospital Graz	Graz
Austria	Medical University of Vienna	Vienna
Austria	SMZ-Süd/Kaiser-Franz-Josef-Spital	Vienna
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	Juravinski Cancer Centre	Hamilton,	Ontario
Canada	McGill - Gerald Bronfman Centre for Clinical Research in Oncology -	Montreal	Quebec
Canada	Montreal Neurological Institute	Montreal	Quebec
Canada	Notre-Dame Hospital (CHUM)	Montreal	Quebec
Canada	The Ottawa Hospital Cancer Centre	Ottawa	Ontario
Canada	(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie	Sherbrooke	Quebec
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Czech Republic	Na Homolce Hospital	Prague
France	CHU Amiens Sud-Salouel	Amiens
France	CHU Angers	Angers
France	Hôpital Saint André Centre Hospitalier Universitaire (CHU) des Hôpitaux de Bordeaux	Bordeaux
France	Hospital of Neurology Pierre Wertheimer	Lyon
France	Group Hospitals Pitie-Salpetriere	Paris
France	Centre Hospitalo-Universitaire de Toulouse Purpan	Toulouse
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	Medical University Heidelberg	Heidelberg
Germany	University Hospital of Schleswig-Holstein	Kiel
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Az. Ospedaliero-Universitaria - Ospedali Riuniti	Ancona
Italy	Ospedale Lecco	Lecco
Italy	C. Besta Neurological Institute	Milan
Italy	Foundation Hospital Greater Policlinico	Milan
Italy	Istituti Fisioterapici Ospitalieri - Istituto Nazionale dei Tumori Regina Elena	Rome
Korea, Republic of	Asan Medical Center	Asan
Korea, Republic of	Yeungnam University Hospital	Daegu
Korea, Republic of	Chungnam National University Hospital (CNUH)	Daejeon
Korea, Republic of	Samsung Medical Center (SMC)	Seoul
Korea, Republic of	Seoul National University Bundang Hospital (SNUBH)	Seoul
Korea, Republic of	Seoul National University Hospital (SNUH)	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital (CMC Seoul)	Seoul
Korea, Republic of	Yonsei University Severance Hospital (YUHS)	Seoul
Korea, Republic of	Ajou University Hospital (AUH)	Suwon
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari de Bellvitge-ICO Duran i Reynals	Barcelona
Spain	Fundacion Jimenes Diaz	Madrid
Spain	Hospital 12 de Octubre, Servicio de Oncología Médica	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Clínica Universidad de Navarra	Pamplona
Sweden	Karolinska Institute	Stockholm
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne
Switzerland	UniversitätsSpital Zürich	Zurich
United States	Emory University, Winship Cancer Institute	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Lahey Clinic Medical Center	Burlington	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University of Illinois at Chicago (UIC)	Chicago	Illinois
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	The Ohio State University Arthur G. James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	Baylor	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Geisinger Health System	Danville	Pennsylvania
United States	Henry Ford Health System	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	New Jersey Neuroscience Center - JFK Medical Center	Edison	New Jersey
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Methodist Hospital	Houston	Texas
United States	Methodist Neurological Institute	Houston	Texas
United States	The University of Texas Health Science Center at Houston (UTHSC)	Houston	Texas
United States	University of California San Diego Moores Cancer Center (UCSD)	La Jolla	California
United States	University of Kentucky, Markey Cancer Center	Lexington	Kentucky
United States	University of Southern California (USC)	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center, Department of Neurosurgery	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	UF Health Cancer Center at Orlando Health	Orlando	Florida
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Barrow Neurology Clinics	Phoenix	Arizona
United States	University of Pittsburgh Medical Center (UPMC)	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Scarborough	Maine
United States	Swedish Neuroscience Institute	Seattle	Washington
United States	University of Washington/Seattle Cancer Care Alliance	Seattle	Washington
United States	Washington University School of Medicine, Division of Oncology	St. Louis	Missouri
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida
United States	Scott and White Healthcare	Temple	Texas
United States	Memorial Hermann The Woodlands	The Woodlands	Texas

Sponsors (1)

Lead Sponsor	Collaborator
NovoCure Ltd.

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czech Republic,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Spain,  Sweden,  Switzerland, 

References & Publications (5)

Kirson ED, Dbalý 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. 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. — View Citation

Kirson ED, Schneiderman RS, Dbalý V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009 Jan 8;9:1. doi: 10.1186/1756-6649-9-1. — View Citation

Salzberg M, Kirson E, Palti Y, Rochlitz C. A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008 Jul;31(7):362-5. doi: 10.1159/000137713. Epub 2008 Jun 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) time		5 years
Secondary	Overall survival (OS)		5 years

External Links

•   Publication in Jama