Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
Keywords
adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, recurrent adult brain tumor, Bevacizumab-naive, NovoTTF-100A
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.
Interventions
BIOLOGICALBevacizumab
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.
DEVICENovoTTF-l00A
NovoTTF-100A will be worn continuously.
OTHERQuality of Life Assessment
Functional Assessment of Cancer Therapy including Brain Tumor module (FACT-Br) questionnaire
Sponsors
NovoCure Ltd.
Case Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab and NovoTTF-100A 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: 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.
NovoTTF-l00A: NovoTTF-100A will be worn continuously.
Quality of Life Assessment: Functional Assessment of Cancer Therapy including Brain Tumor module (FACT-Br) questionnaire | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Screen failure | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bevacizumab and NovoTTF-100A |
|---|---|
| Age, Customized 10-19 years | 1 Participants |
| Age, Customized 20-29 years | 0 Participants |
| Age, Customized 30-39 years | 1 Participants |
| Age, Customized 40-49 years | 2 Participants |
| Age, Customized 50-59 years | 5 Participants |
| Age, Customized 60-69 years | 8 Participants |
| Age, Customized 70-79 years | 1 Participants |
| Age, Customized unknown | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 25 |
| other Total, other adverse events | 20 / 25 |
| serious Total, serious adverse events | 5 / 25 |
Outcome results
Primary
Percent of Participants With 6-month Progression-free Survival (PFS6)
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.
Time frame: 6 months
Population: Participants eligible for analysis (completed study)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Percent of Participants With 6-month Progression-free Survival (PFS6) | 33 percent of participants |
Secondary
Change From Baseline in Quality of Life (QOL) as Measured by FACT-BR Score
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.
Time frame: Baseline, 30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)
Population: Only 5 participants had QOL change from baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Change From Baseline in Quality of Life (QOL) as Measured by FACT-BR Score | 6 scores on a scale |
Secondary
Median Overall Survival
Median overall survival (OS) in months
Time frame: 30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)
Population: Participants eligible for analysis (completed study)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Median Overall Survival | 10.5 months |
Secondary
Median Time-to-progression
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 frame: 30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)
Population: Participants eligible for analysis (completed study)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Median Time-to-progression | 4.1 months |
Secondary
Number of Participants Experiencing Grade 3/4 Toxicities Related to Therapy Combination Per by CTCAE Version 4.0.
Number of participants experiencing grade 3 or 4 toxicities related to therapy combination per by CTCAE version 4.0.
Time frame: 5 years, 9 months
Population: All participants enrolled in study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Number of Participants Experiencing Grade 3/4 Toxicities Related to Therapy Combination Per by CTCAE Version 4.0. | 2 Participants |
Secondary
Objective Response Rate (ORR) Based on RANO Criteria
ORR as defined by the modified Response Assessment in Neuro-Oncology (RANO) criteria.
Time frame: 30 days after treatment completion through study completion, an average of 5 years, 9 months
Population: Only 16 of the 25 participants were analyzed because 9 participants were not evaluable.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab and NovoTTF-100A | Objective Response Rate (ORR) Based on RANO Criteria | Complete Response | 1 Participants |
| Bevacizumab and NovoTTF-100A | Objective Response Rate (ORR) Based on RANO Criteria | Partial Response | 3 Participants |
| Bevacizumab and NovoTTF-100A | Objective Response Rate (ORR) Based on RANO Criteria | Stable Disease | 6 Participants |
| Bevacizumab and NovoTTF-100A | Objective Response Rate (ORR) Based on RANO Criteria | Progressive Disease | 6 Participants |
Secondary
Percent of Participants With 12-month Progression-free Survival
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.
Time frame: 12 months
Population: Participants eligible for analysis (completed study)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Percent of Participants With 12-month Progression-free Survival | 19 percent of participants |
Secondary
Time to Reliable Change in Neurocognitive Function (NCF)
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.
Time frame: 30 days after treatment completion (Treatment continued until disease progression in the brain, death, or unacceptable side effects to patient)
Population: Only 2 participants reached reliable NCF change.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab and NovoTTF-100A | Time to Reliable Change in Neurocognitive Function (NCF) | 1.9 months |