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

Sponsor

NovoCure Ltd. (Industry)

Overall Status

Completed

CT.gov ID

NCT00916409

Collaborator

(none)

700

Enrollment

Locations

Arms

Duration (Months)

7.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Device: NovoTTF-100A device Drug: Temozolomide	Phase 3

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:

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2009

Actual Primary Completion Date :

Dec 1, 2016

Actual Study Completion Date :

Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NovoTTF-100A device in combination with Temozolomide 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.	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.
Active Comparator: Temozolomide alone, as the best known standard of care Patients will be treated with Temozolomide, as the best known standard of care for Glioblastoma Multiforme patients.	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.

Arm

Intervention/Treatment

Experimental: NovoTTF-100A device in combination with Temozolomide

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.

Device: NovoTTF-100A device

Active Comparator: Temozolomide alone, as the best known standard of care

Patients will be treated with Temozolomide, as the best known standard of care for Glioblastoma Multiforme patients.

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.

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) time [5 years]

Secondary Outcome Measures

Overall survival (OS) [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Pathological evidence of GBM using WHO classification criteria.
18 years of age.
Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):
Patients may enroll in the study if received Gliadel wafers before entering the trial
Any additional treatments received prior to enrollment will be considered an exclusion.
Minimal dose for concomitant radiotherapy is 45 Gy
Karnofsky scale ≥ 70
Life expectancy at least 3 months
Participants of childbearing age must use effective contraception.
All patients must sign written informed consent.
Treatment start date at least 4 weeks out from surgery.
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:

Progressive disease (according to MacDonald Criteria). If pseudoprogression is suspected, additional imaging studies must be performed to rule out true progression.
Actively participating in another clinical treatment trial
Pregnant
Significant co-morbidities at baseline which would prevent maintenance Temozolomide treatment:
Thrombocytopenia (platelet count < 100 x 103/μL)
Neutropenia (absolute neutrophil count < 1.5 x 103/μL)
CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)
Significant liver function impairment - AST or ALT > 3 times the upper limit of normal
Total bilirubin > upper limit of normal
Significant renal impairment (serum creatinine > 1.7 mg/dL)
Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
Infra-tentorial tumor
Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness)
History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity to DTIC.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-3410
2	Barrow Neurology Clinics	Phoenix	Arizona	United States	85013
3	City of Hope	Duarte	California	United States	91010-3000
4	University of California San Diego Moores Cancer Center (UCSD)	La Jolla	California	United States	92093
5	University of Southern California (USC)	Los Angeles	California	United States	90033
6	University of Colorado Denver	Aurora	Colorado	United States	80045
7	UF Health Cancer Center at Orlando Health	Orlando	Florida	United States	32806
8	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
9	Emory University, Winship Cancer Institute	Atlanta	Georgia	United States	30322
10	University of Illinois at Chicago (UIC)	Chicago	Illinois	United States	60612
11	University of Kentucky, Markey Cancer Center	Lexington	Kentucky	United States	40536-0093
12	Norton Cancer Institute	Louisville	Kentucky	United States	40202
13	Maine Medical Center	Scarborough	Maine	United States	04074
14	The Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
15	Tufts Medical Center	Boston	Massachusetts	United States	02111
16	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
17	Lahey Clinic Medical Center	Burlington	Massachusetts	United States	01805
18	Henry Ford Health System	Detroit	Michigan	United States	48202
19	Washington University School of Medicine, Division of Oncology	St. Louis	Missouri	United States	63110
20	New Jersey Neuroscience Center - JFK Medical Center	Edison	New Jersey	United States	08818
21	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	Weill Cornell Medical College	New York	New York	United States	10021
23	Mount Sinai Medical Center, Department of Neurosurgery	New York	New York	United States	10029
24	Columbia University Medical Center	New York	New York	United States	10032
25	University of North Carolina	Chapel Hill	North Carolina	United States	27599
26	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
27	The Ohio State University Arthur G. James Cancer Hospital and Solove Research Institute	Columbus	Ohio	United States	43210
28	Geisinger Health System	Danville	Pennsylvania	United States	17822
29	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
30	Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19104
31	University of Pittsburgh Medical Center (UPMC)	Pittsburgh	Pennsylvania	United States	15232
32	UT Southwestern Medical Center	Dallas	Texas	United States	75235-8808
33	Baylor	Dallas	Texas	United States	75246
34	Methodist Hospital	Houston	Texas	United States	77030
35	Methodist Neurological Institute	Houston	Texas	United States	77030
36	The University of Texas Health Science Center at Houston (UTHSC)	Houston	Texas	United States	77030
37	Scott and White Healthcare	Temple	Texas	United States	76508
38	Memorial Hermann The Woodlands	The Woodlands	Texas	United States	77380
39	University of Virginia Health System	Charlottesville	Virginia	United States	22908
40	Swedish Neuroscience Institute	Seattle	Washington	United States	98122
41	University of Washington/Seattle Cancer Care Alliance	Seattle	Washington	United States	98195
42	University Hospital Graz	Graz		Austria
43	Medical University of Vienna	Vienna		Austria
44	SMZ-Süd/Kaiser-Franz-Josef-Spital	Vienna		Austria
45	Tom Baker Cancer Center	Calgary	Alberta	Canada	T2N 4N2
46	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
47	Juravinski Cancer Centre	Hamilton,	Ontario	Canada	L8V5C2
48	The Ottawa Hospital Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
49	Notre-Dame Hospital (CHUM)	Montreal	Quebec	Canada	H2L 4 M1
50	Montreal Neurological Institute	Montreal	Quebec	Canada	H3A 2B4
51	McGill - Gerald Bronfman Centre for Clinical Research in Oncology -	Montreal	Quebec	Canada	H3T 1E2
52	(CHUS) Centre Hospitalier Universitaire de Sherbrooke, Service de Neurochirurgie	Sherbrooke	Quebec	Canada	J1H 5N4
53	Na Homolce Hospital	Prague		Czech Republic
54	CHU Amiens Sud-Salouel	Amiens		France
55	CHU Angers	Angers		France
56	Hôpital Saint André Centre Hospitalier Universitaire (CHU) des Hôpitaux de Bordeaux	Bordeaux		France
57	Hospital of Neurology Pierre Wertheimer	Lyon		France
58	Group Hospitals Pitie-Salpetriere	Paris		France
59	Centre Hospitalo-Universitaire de Toulouse Purpan	Toulouse		France
60	University Medical Center Hamburg-Eppendorf	Hamburg		Germany
61	Medical University Heidelberg	Heidelberg		Germany
62	University Hospital of Schleswig-Holstein	Kiel		Germany
63	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel
64	Az. Ospedaliero-Universitaria - Ospedali Riuniti	Ancona		Italy
65	Ospedale Lecco	Lecco		Italy
66	C. Besta Neurological Institute	Milan		Italy
67	Foundation Hospital Greater Policlinico	Milan		Italy
68	Istituti Fisioterapici Ospitalieri - Istituto Nazionale dei Tumori Regina Elena	Rome		Italy
69	Asan Medical Center	Asan		Korea, Republic of
70	Yeungnam University Hospital	Daegu		Korea, Republic of
71	Chungnam National University Hospital (CNUH)	Daejeon		Korea, Republic of
72	Samsung Medical Center (SMC)	Seoul		Korea, Republic of
73	Seoul National University Bundang Hospital (SNUBH)	Seoul		Korea, Republic of
74	Seoul National University Hospital (SNUH)	Seoul		Korea, Republic of
75	The Catholic University of Korea, Seoul St. Mary's Hospital (CMC Seoul)	Seoul		Korea, Republic of
76	Yonsei University Severance Hospital (YUHS)	Seoul		Korea, Republic of
77	Ajou University Hospital (AUH)	Suwon		Korea, Republic of
78	Hospital Universitari Germans Trias i Pujol	Badalona		Spain
79	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain
80	Hospital del Mar	Barcelona		Spain
81	Hospital Universitari de Bellvitge-ICO Duran i Reynals	Barcelona		Spain
82	Fundacion Jimenes Diaz	Madrid		Spain
83	Hospital 12 de Octubre, Servicio de Oncología Médica	Madrid		Spain
84	Hospital Clinico San Carlos	Madrid		Spain
85	Hospital Universitario Ramon y Cajal	Madrid		Spain
86	Clínica Universidad de Navarra	Pamplona		Spain
87	Karolinska Institute	Stockholm		Sweden
88	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne		Switzerland
89	UniversitätsSpital Zürich	Zurich		Switzerland

Sponsors and Collaborators

NovoCure Ltd.

Investigators

Study Director: Roger Stupp, MD, University Hospital, Zürich
Study Director: Philip H. Gutin, MD, Memorial Sloan Kettering Cancer Center
Study Director: Eric T. Wong, MD, Beth Israel Deaconess Medical Center
Study Director: Herbert H. Engelhard, MD, PhD, University of Illinois at Chicago
Study Director: Manfred Westphal, Prof. MD, Universitätsklinikum Hamburg-Eppendorf