A Phase II Study of Optune (NovoTTF) in Combination With Bevacizumab (BEV) and Temozolomide (TMZ) in Patients With Newly Diagnosed Unresectable Glioblastoma (GBM)

A Phase II Study of Optune (NovoTTF) in Combination With Bevacizumab (BEV) and Temozolomide (TMZ) in Patients With Newly Diagnosed Unresectable Glioblastoma (GBM)

All patients will complete best standard of care radiation, temozolomide and bevacizumab (6 weeks). Within two weeks of completion of this initial treatment period, study patients will be fitted with the NovoTTF-100A System and treated continuously. They will be treated with TTFields for 12 months for an average of 18 hours per day. The patient may elect to take a treatment break for a total of 3 days per month, for each month and still be in compliance. This will consist of wearing four electrically insulated electrode arrays on the head. The patients will also continue with maintenance temozolomide/ bevacizumab.

This study will be carried out in two stages. The first stage will enroll a cohort of 22 patients. The FDA will review safety data of the first 15 patients during enrollment of the first cohort. Enrollment and interim analysis of the first cohort of patients will be completed within 15 months of study commencement. Upon FDA approval and favorable interim analysis followed by subsequent protocol/consent amendment (as applicable), the second stage will enroll a cohort of 24 patients and will be completed within 15 months of stage 2 commencement. The overall duration of the study is expected to be no longer than 30 months.

Inclusion Criteria:

• At least 22 years of age
• Have undergone a brain biopsy via stereotactic or open technique
• Pathological evidence of GBM using WHO classification criteria
• Planned 6 weeks of concurrent chemoradiotherapy post-biopsy concomitant with temozolomide (45-70Gy)
• Karnofsky scale greater than or equal to 70
• Life expectancy at least 3 months
• Baseline hemoglobin of > 8.0 gm/dL (with or without transfusion)
• Adequate coagulation defined as PT and INR < 1.5 times the upper limit of normal
• Signed informed consent
• Able to start bevacizumab at least 2 weeks but no more than 4 weeks from date of biopsy
• Able to tolerate MRI of brain and have measurable disease.
• Participants of childbearing age must use effective contraception for at least 6 months following completion of treatment.

Exclusion Criteria

• Enrolled in another clinical treatment trial
• Pregnant or Breast-feeding
• Any other malignancy aside from localized basal cell or squamous cell carcinoma of the skin
• Significant co-morbidities at baseline which would prevent maintenance temozolomide
• Thrombocytopenia (platelet count < 100 x 103 )
• Neutropenia (absolute neutrophil count < 1.5 x 103 )
• 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> 2 times the 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 or hydrogel
• Inability to adequately cover treatment area with TTFields (Tumor Treating Fields)
• Inability to wear NovoTTF-100A System for an average of 18 hours per 24 hours
• Currently taking cytotoxic medications, non-steroidal ant-inflammatory drugs (NSAIDS), or enzyme inducing anticonvulsants.
• Currently taking anticoagulants or blood-thinners (Coumadin)
• Subjects meeting any of the following bevacizumab-specific contraindications are ineligible for study entry:
• Inadequately controlled hypertension (defined as systolic blood pressure greater than or equal to 150 and/or diastolic blood pressure > 100 mmHg)
• Prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to study enrollment
• History of stroke or transient ischemic attack within 6 months prior to study enrollment
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study enrollment
• History of hemoptysis (greater than or equal to a half teaspoon of bright red blood per episode) within 1 month prior to study enrollment
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• Major surgical procedure or significant traumatic injury within 28 days prior to 1st bevacizumab infusion or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
• History of abdominal fistula, gastrointestinal perforation within 6 months prior to study enrollment
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Proteinuria at screening as demonstrated by either urine protein: creatinine (UPC) ratio greater than or equal to 1.0 at screening OR urine dipstick for proteinuria greater than or equal to 2 or more (patients discovered to have greater than or equal to 2 or greater proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate less than or equal to 1g of protein in 24 hours to be eligible).
• Known hypersensitivity to any component of bevacizumab