NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma

Phase 2

Completed

Conditions: Adult Giant Cell Glioblastoma
Recurrent Adult Brain Tumor
Adult Gliosarcoma
Adult Glioblastoma

Interventions: Biological: Bevacizumab
Device: NovoTTF-l00A
Other: Quality of Life Assessment

Registration Number: NCT01894061

Lead Sponsor: Case Comprehensive Cancer Center

Brief Summary: NovoTTF-100A is a device and Bevacizumab is a study drug that have both been approved by the FDA (Food and Drug Administration) for use as monotherapy in treating glioblastoma multiforme. The NovoTTF-l00A is a portable battery operated device which produces TTFields within the human body using surface electrodes (transducer arrays). Intermediate frequency electric fields (TTFields) stunt the growth of tumor cells.

The purpose of this study is to determine the efficacy of the combination of Bevacizumab and NovoTTF-100A in Bevacizumab naive (meaning have never received bevacizumab before) patients with recurrent glioblastoma (GBM) as measured by 6-month progression free survival.

Detailed Description: This will be an open label Phase II trial in adults with recurrent glioblastoma (GBM). The NovoTTF-100A treatment and Bevacizumab will be administered on an outpatient basis; NovoTTF-100A treatment will be initiated in the outpatient clinic.

PRIMARY OBJECTIVES:

I. To determine the efficacy of the combination of bevacizumab and NovoTTF-100A in bevacizumab-naive patients with recurrent glioblastoma (GBM) as measured by 6-month progression-free survival (PFS6).

SECONDARY OBJECTIVES:

I. To assess safety and tolerability of the combination of bevacizumab and Novo-TTF-100A in this patient population.

II. To evaluate overall survival in this population. III. To determine objective response rate (ORR) by modified Revised Assessment in Neuro-Oncology (RANO) criteria in this population.

IV. To assess time-to-progression in this population. V. To assess neurocognitive function (NCF) and quality of life (QOL) in this population.

OUTLINE:

Patients receive bevacizumab intravenously (IV) on days 1 and 15. Patients also undergo electric field therapy with NovoTTF-100A for at least 18 hours daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 28 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Patients with histologically confirmed glioblastoma or other grade IV malignant glioma (i.e. gliosarcoma, small cell glioblastoma, etc.), recurrent after prior external-beam fractionated radiotherapy and temozolomide chemotherapy.
Patients with up to two prior recurrences are allowed.
Karnofsky performance status ≥70.
Patients must have the following laboratory values:
- Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
- Platelets ≥ 100 x 10^9/L
- Hemoglobin (Hgb) > 9 g/dL
- Serum total bilirubin: ≤ 1.5 x ULN
- ALT and AST ≤ 3.0 x ULN
- Serum creatinine ≤ 1.5 x ULN
- Blood coagulation parameters: INR ≤ 1.5
Minimum interval since completion of radiation treatment is 12 weeks
Minimum interval since last drug therapy:
- 3 weeks since last non-cytotoxic therapy
- 3 weeks must have elapsed since the completion of a non-nitrosourea-containing chemotherapy regimen
- 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen.
Patients must have signed an approved informed consent and authorization permitting release of personal health information.
Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. The effects of bevacizumab on developing fetus or nursing infant are not known. Female patients of child-bearing potential must have a negative pregnancy test.
Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Patients with other prior malignancies must be disease-free for ≥ three years.
Patients must be maintained on a stable corticosteroid regimen from the time of their baseline scan until the start of treatment and/or for at least 5 days before starting treatment.

Exclusion Criteria

Patients who have had previous treatment with bevacizumab, and or NovoTTF 100A system.
Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:
- History or presence of serious uncontrolled ventricular arrhythmias
- Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
- Uncontrolled hypertension (defined by a systolic blood pressure (SBP) ≥ 160 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg while on anti-hypertensive medications)
Patients with cirrhosis, or active viral or nonviral hepatitis.
Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain or documented clinically significant arrhythmias.
Infra-tentorial tumor
Evidence of increased intracranial pressure (clinically significant papilledema, vomiting and nausea or reduced level of consciousness)
Known sensitivity to conductive hydrogels
Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
Pregnant or breast-feeding women
Patients unwilling or unable to comply with the protocol
Patients with leptomeningeal disease

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bevacizumab and NovoTTF-100A	Bevacizumab	Bevacizumab will be administered intravenously on days 1 and 15 of each 28 day cycle.The dose of bevacizumab will be 10 mg/kg of actual body weight.
Bevacizumab and NovoTTF-100A	Quality of Life Assessment	Bevacizumab will be administered intravenously on days 1 and 15 of each 28 day cycle.The dose of bevacizumab will be 10 mg/kg of actual body weight.
Bevacizumab and NovoTTF-100A	NovoTTF-l00A	Bevacizumab will be administered intravenously on days 1 and 15 of each 28 day cycle.The dose of bevacizumab will be 10 mg/kg of actual body weight.

Primary Outcome Measures

Name	Time	Method
Percent of Participants With 6-month Progression-free Survival (PFS6)	6 months	Efficacy of therapy as measured by percent of participants with (PFS6). This trial will be considered successful if at least 20% of participants achieve PFS at 6 months. Disease progression is defined by RANO criteria. In cases where the RANO criteria cannot be applied, progression should be based on unequivocal evidence of progressive disease sufficient to require a change in therapy. The Modified RANO criteria are a set of guidelines for evaluating treatment response clinical trials. Modified RANO Response Criteria include levels of response including Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable Disease (SD), or Progressive Disease.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) Based on RANO Criteria	30 days after treatment completion through study completion, an average of 5 years, 9 months	ORR as defined by the modified Response Assessment in Neuro-Oncology (RANO) criteria.
Number of Participants Experiencing Grade 3/4 Toxicities Related to Therapy Combination Per by CTCAE Version 4.0.	5 years, 9 months	Number of participants experiencing grade 3 or 4 toxicities related to therapy combination per by CTCAE version 4.0.
Median Overall Survival	30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)	Median overall survival (OS) in months
Median Time-to-progression	30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)	Median time to progression by Kaplan Meier methodology. Disease progression is defined by RANO criteria. In cases where the RANO criteria cannot be applied, progression should be based on unequivocal evidence of progressive disease sufficient to require a change in therapy. The Modified RANO criteria are a set of guidelines for evaluating treatment response clinical trials. Modified RANO Response Criteria include levels of response including Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable Disease (SD), or Progressive Disease.
Time to Reliable Change in Neurocognitive Function (NCF)	30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)	Time to reliable change in NCF by Kaplan Meier methodology. Memory, verbal fluency, visual-motor speed, executive function and motor dexterity tests will be administered. NCF testing involves standardized psychometric instruments that are sensitive to the neurotoxic effects of cancer treatment in brain tumor clinical trials.
Change From Baseline in Quality of Life (QOL) as Measured by FACT-BR Score	Baseline, 30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)	Functional Assessment of Cancer Therapy including Brain Tumor module (FACT-Br) is a 54-item questionnaire that has four areas of cumulative measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-Br total score ranges between 0 and 76. The higher the score, the better the quality of life.
Percent of Participants With 12-month Progression-free Survival	12 months	Efficacy of therapy as measured by percent of participants with 12-month PFS. Disease progression is defined by modified RANO criteria. In cases where the modified RANO criteria cannot be applied, progression should be based on unequivocal evidence of progressive disease sufficient to require a change in therapy. The Modified RANO criteria are a set of guidelines for evaluating treatment response clinical trials. Modified RANO Response Criteria include levels of response including Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable Disease (SD), or Progressive Disease.

Trial Locations

Locations (3): University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center
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Cleveland, Ohio, United States
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
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Cleveland, Ohio, United States
University of Cincinnati
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Cincinnati, Ohio, United States