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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cancer of Brain and Nervous System

Intervention / Treatment
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* Device: NovoTTF100A
* Drug: Bevacizumab
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Planned RT + TMZ + BEV + NovoTTF100A Device<br>Best standard of care radiation therapy (RT, 2 Gy given daily 5 days per week), temozolomide (TMZ, 75 mg/m2 administered daily), and bevacizumab (BEV, 10 mg/kg administered every 2 weeks as an IV infusion) for 6 weeks. After completion of chemoradiation, NovoTTF100A system was initiated, to be worn on average 18 hours or more a day for up to 12 months. The patients also continued with maintenance TMZ/BEV. | Device: NovoTTF100A<br> <br> * Other names: Optune(TM);Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Temozolomide<br> <br> * Other names: Temodar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 12-Month Survival | Twelve-month survival was determined for each subject as a binary variable indicating whether or not the subject was alive at 12 months from initiation of chemoradiation. Determination of this endpoint occurs after the subject has at least 12 months of follow-up, unless they have died sooner. | Evaluated over 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was defined as the duration from the initiation of chemoradiation therapy to the date of death from any cause. Subjects who were alive or lost to follow-up at the time of the analysis were be censored at the last known date they were alive. | From date of treatment start to date of death, or censored as described above; assessed for approximately 5 years | 
| Progression Free Survival (PFS) | Progression-Free Survival (PFS) is defined as duration of time from initiation of chemoradiation therapy to first occurrence of either progressive disease (PD) or death. PD must be objectively determined as per RANO criteria (Updated Response Assessment Criteria for High Grade Gliomas, where PD is defined as a 25% increase in sum of products of diameters from nadir), where date of PD is date of assessment that identified PD. If subject died without documented PD, date of progression will be date of death. For surviving subjects who do not have documented PD, PFS will be censored at date of last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last radiologic assessment prior to the commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments. | From date of treatment start to date of progression/death, or censored as described above; assessed for approximately 2 years. | 
| Number of Participants With Objective Response | Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by the Updated Response Assessment Criteria for High Grade Gliomas (RANO; where CR is indicated by disappearance of all target lesions and PR is indicated by >=50% decrease in the sum of products of diameters of target lesions with baseline as reference). Best responses of CR or PR must be confirmed by a subsequent radiologic assessment. | From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 7 months) | 
| Number of Participants With Disease Control | Disease control was determined for each subject indicating whether or not they achieved an overall response of stable disease (SD) or better by RANO criteria (where a CR is indicated by disappearance of all target and non target lesions, a PR is indicated by >= 50% decrease in sum of products of diameters of target lesions with baseline as reference, and SD is neither sufficient shrinkage to qualify for PR nor sufficient growth, >=25%, to indicate progression). | From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 7 months). | 
| Duration of Response | Duration of response (DOR) was measured from the time RANO criteria are met for CR or PR (whichever is first recorded) until the first occurrence of either progressive disease or death. PD must be objectively determined as per RANO criteria (Updated Response Assessment Criteria for High Grade Gliomas, where PD is defined as a 25% increase in sum of products of diameters from nadir), where PD date is assessment date that identified PD. If subject died without PD, PD date was death date. For surviving subjects who didn't have documented PD, DOR was censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, DOR was censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who had an initial PD event immediately following 2 or more consecutive missed assessments were censored at last assessment prior to missed assessments. DOR was only calculated for subjects with a best response of PR or CR. | From date of first response to date of progression/death, or censored as described above; assessed for approximately 2 years. | 
| Duration of Disease Control | Duration of disease control (DoDC) was measured from the time of initiation of chemoradiation therapy until the first occurrence of either progressive disease or death. PD must be objectively determined as per RANO criteria (Updated Response Assessment Criteria for High Grade Gliomas, where PD is defined as a 25% increase in sum of products of diameters from nadir), where PD date is assessment date that identified PD. If subject died without PD, PD date was death date. For surviving subjects who didn't have documented PD, DoDC was censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, DoDC was censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who had an initial PD event immediately following 2 or more consecutive missed assessments were censored at last assessment prior to missed assessments. DoDC was calculated only for subjects with a best overall response of SD or better. | From date of treatment start to date of progression/death, or censored as described above; assessed for approximately 2 years. |