Clinical trial NCT00916409: Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM)
Official title: A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients With Newly Diagnosed GBM.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Glioblastoma Multiforme
Keywords: Glioblastoma Multiforme
Glioblastoma
GBM
Brain tumor
Treatment
Minimal toxicity
Newly Diagnosed
TTFields
Tumor Treating Fields
NovoCure
Lead sponsor: NovoCure Ltd.
Sponsor class: INDUSTRY
First posted: 2009-06-09
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS) time
timeFrame: 5 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurology Clinics
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center (UCSD)
state: California
city: Los Angeles
country: United States
facility: University of Southern California (USC)
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Orlando
country: United States
facility: UF Health Cancer Center at Orlando Health
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University, Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago (UIC)
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky, Markey Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: St. Louis
country: United States
facility: Washington University School of Medicine, Division of Oncology
state: Missouri
city: Edison
country: United States
facility: New Jersey Neuroscience Center - JFK Medical Center
state: New Jersey
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center, Department of Neurosurgery
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Arthur G. James Cancer Hospital and Solove Research Institute
state: Ohio
city: Danville
country: United States
facility: Geisinger Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC)
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Dallas
country: United States
facility: Baylor
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Methodist Neurological Institute
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston (UTHSC)
state: Texas
city: Temple
country: United States
facility: Scott and White Healthcare
state: Texas
city: The Woodlands
country: United States
facility: Memorial Hermann The Woodlands
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: Swedish Neuroscience Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington/Seattle Cancer Care Alliance
state: Washington
city: Graz
country: Austria
facility: University Hospital Graz
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Vienna
country: Austria
facility: SMZ-Süd/Kaiser-Franz-Josef-Spital
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Hamilton,
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Notre-Dame Hospital (CHUM)
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute
state: Quebec
city: Montreal
country: Canada
facility: McGill - Gerald Bronfman Centre for Clinical Research in Oncology -
state: Quebec
city: Sherbrooke
country: Canada
facility: (CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie
state: Quebec
city: Prague
country: Czech Republic
facility: Na Homolce Hospital
city: Amiens
country: France
facility: CHU Amiens Sud-Salouel
city: Angers
country: France
facility: CHU Angers
city: Bordeaux
country: France
facility: Hôpital Saint André Centre Hospitalier Universitaire (CHU) des Hôpitaux de Bordeaux
city: Lyon
country: France
facility: Hospital of Neurology Pierre Wertheimer
city: Paris
country: France
facility: Group Hospitals Pitie-Salpetriere
city: Toulouse
country: France
facility: Centre Hospitalo-Universitaire de Toulouse Purpan
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Medical University Heidelberg
city: Kiel
country: Germany
facility: University Hospital of Schleswig-Holstein
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Ancona
country: Italy
facility: Az. Ospedaliero-Universitaria - Ospedali Riuniti
city: Lecco
country: Italy
facility: Ospedale Lecco
city: Milan
country: Italy
facility: C. Besta Neurological Institute
city: Milan
country: Italy
facility: Foundation Hospital Greater Policlinico
city: Rome
country: Italy
facility: Istituti Fisioterapici Ospitalieri - Istituto Nazionale dei Tumori Regina Elena
city: Asan
country: Korea, Republic of
facility: Asan Medical Center
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Hospital
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital (CNUH)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center (SMC)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Bundang Hospital (SNUBH)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital (SNUH)
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital (CMC Seoul)
city: Seoul
country: Korea, Republic of
facility: Yonsei University Severance Hospital (YUHS)
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital (AUH)
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge-ICO Duran i Reynals
city: Madrid
country: Spain
facility: Fundacion Jimenes Diaz
city: Madrid
country: Spain
facility: Hospital 12 de Octubre, Servicio de Oncología Médica
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Stockholm
country: Sweden
facility: Karolinska Institute
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Zurich
country: Switzerland
facility: UniversitätsSpital Zürich
Study officials:
affiliation: University Hospital, Zürich
name: Roger Stupp, MD
role: STUDY_DIRECTOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Philip H. Gutin, MD
role: STUDY_DIRECTOR
affiliation: Beth Israel Deaconess Medical Center
name: Eric T. Wong, MD
role: STUDY_DIRECTOR
affiliation: University of Illinois at Chicago
name: Herbert H. Engelhard, MD, PhD
role: STUDY_DIRECTOR
affiliation: Universitätsklinikum Hamburg-Eppendorf
name: Manfred Westphal, Prof. MD
role: STUDY_DIRECTOR
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