• Overall survival (OS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Progression free survival at 6 months (PFS6) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• 1% and 2-year survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Radiological response (Macdonald criteria) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Quality of life assessment (EORTC QLQ-C30) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Adverse events severity and frequency [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

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) to the region of the malignant tumor, by means of surface, insulated electrodes.

PAST CLINICAL EXPERIENCE:

The effect of the electric fields generated by the NovoTTF-100A device (TTFields) has been tested in a small scale pilot trial in 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 trials is 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. The recruitment of 236 patients to another ongoing clinical trial (designated EF-11) designed to test the efficacy and safety of the NovoTTF-100A in recurrent GBM, has recently completed.

DESCRIPTION OF THE TRIAL:

Newly diagnosed GBM patients who:

• Underwent a biopsy or surgery followed by radiation therapy in combination with Temozolomide chemotherapy, AND

• Meet all of the requirements for participation in the study 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 who meet inclusion/exclusion criteria 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). If assigned to the NovoTTF-100A in combination with Temozolomide group, the patients will be treated continuously with the device, as long as under the treatment with Temozolomide and a second line of treatment the disease remains stable or regressing. Such second line could 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 electrodes on the head. Electrode placement will require shaving of the scalp before 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 under the treatment with a second line of 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 and ECG will be performed. A routine MRI of the head will be performed at baseline and every second month thereafter. 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.

• 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 electrodes 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.

• 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 electrodes on the head. The treatment enables the patient to maintain regular daily routine.
  Intervention: 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.
  Intervention: Drug: Temozolomide

• 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.
• 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. Epub 2007 Jun 5.
• 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. Epub 2008 Jun 24.
• 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 Apr 23; [Epub ahead of print]
• 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.

Inclusion Criteria:

• Pathological evidence of GBM using WHO classification criteria
• > 18 years of age
• Received maximal debulking surgery and radiotherapy with Temozolomide (any additional treatments received prior to enrollment will be considered an exclusion)
• 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 last dose of adjuvant Temozolomide
• Treatment start date at least 4 weeks out from radiation therapy

Exclusion Criteria:

• Progressive disease (according to MacDonald Criteria)
• Actively participating in another clinical treatment trial
• Pregnant

• 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)
• Implanted pacemaker, defibrillator or deep brain stimulator, 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