Glioblastoma Multiforme, Glioblastoma, Malignant Glioma, GBM
Conditions
Brief summary
Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant neoplasm of the central nervous system in adults. Despite an aggressive multimodality treatment approach including surgery, radiation therapy and chemotherapy, overall survival remains poor. Novocure has shown that when properly tuned, very low intensity, intermediate frequency electric fields (TTFields) stunt the growth of tumor cells. The Optune system (NovoTTFTM Therapy) is a portable battery operated device, which produces TTFields within the human body by means of surface transducer arrays. The TTFields are applied to the patient by means of surface transducer arrays that are electrically insulated, so that resistively coupled electric currents are not delivered to the patient. Optune is currently FDA-approved as a single modality treatment for recurrent GBM when both surgical and radiotherapy options have been exhausted as well as combination with adjuvant temozolomide for newly diagnosed GBM. This research study is being performed to determine whether or not TTFields combined with pulsed bevacizumab treatment increases overall survival in patients with bevacizumab-refractory GBM compared to historical controls treated with continuous bevacizumab alone or in combination with other chemotherapy.
Detailed description
Subjects who have evidence of bevacizumab-refractory GBM will be eligible to participate in this research study. Subjects will undergo 12 months of planned continuous treatment with TTFields followed by pulsed bevacizumab treatment when there is evidence of further progression per RANO, with the option of extending treatment up to a total of 24 months in patients who have not progressed and/or have adequate performance status at the 12 month mark. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. If after one cycle on, there is no evidence of a repeat response; bevacizumab will be continued for one more cycle. If after two cycles on, there is no repeat response; bevacizumab will be continued with or without other standard chemotherapy until death. If after at least one cycle on, there is evidence of repeat response, bevacizumab will be discontinued for at least one cycle or until progression is noted again per RANO, whichever is later, at which time pulsed bevacizumab will be restarted as outlined above. The investigators believe that this approach will produce peaks and troughs in mitotic activities of glioma cells that render glioma cells more sensitive to the antimitotic activity of Optune during peak growth rates, thus lowering disease burden and increasing survival. In addition, the following will be performed: Bevacizumab will be given at 10mg/kg IV every 2 weeks. Physical examination and quality of life (QoL) assessments will be performed bi-monthly. Brain MRI will be performed every 2 months.
Interventions
DRUGBevacizumab
Bevacizumab will be given at 10mg/kg IV every 2 weeks.
DEVICEOptune
Optune will be worn continuously for 12 months. Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, perpendicular field directions at a maximal intensity of 707mARMS. There will be no adjustments made to the device by investigators or patients/caregivers.
OTHERBrain MRI
Brain MRI will be done at screening and every 8 weeks.
OTHERQuality of Life Questionnaires
The quality of life questionnaires will be performed within 14 days of treatment and every 4 weeks.
Sponsors
NovoCure Ltd.
University of Florida
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
* Histologically confirmed GBM, WHO grade IV. GBM variants and secondary GBM are allowed in any recurrence (including multiple) and have been treated with radiation and chemotherapy. * Unequivocal evidence of tumor progression during prior bevacizumab treatment per RANO criteria. * Patient is a candidate for, and agrees to proceed with additional bevacizumab treatment. * Male or female at least 22 years of age or older. * Karnofsky Performance Scale (KPS) ≥ 60%. * Planned treatment with TTFields therapy. * Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of treatment. * Participants of childbearing/reproductive potential must use effective contraception. * Participants must be able to understand and willing to comply with protocol requirements as assessed by the investigator. * Signed informed consent according to institutional guidelines prior to registration.
Exclusion criteria
* Inability to undergo brain MRI due to medical or personal reasons. * Currently receiving investigational agents that are intended as treatments of recurrent GBM. * Skull defect such as missing bone or bullet fragments. * Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, heart attack within the previous 12 months, stroke (except for TIA) within the previous 6 months, or psychiatric illness/social situations that would limit compliance with study requirements. * Intracranial hemorrhage except for tumor associated micro hemorrhage. * Women who are pregnant or breastfeeding. * Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, vagus nerve stimulator, and other implanted electronic devices in the brain or the spinal cord. * Tumor located entirely in the infratentorium. * History of hypersensitivity to hydrogel.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | from date of starting Optune to date of death or censoring, whichever comes first, assessed up to 24 months | Overall survival is defined as time interval from date of starting Optune to date of death or censoring whichever happens first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Karnofsky Performance Scale | Assessed up to 24 months | The Karnofsky Performance Scale is rated from 0 - 100 with 0 = death and 100 = normal without complaints or evidence of disease. A higher score means the patient is better able to carry out daily activities. Patients are evaluable for assessment of QoL after completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period. |
| Mini-Mental Status Exam | Assessed up to 24 months | The Mini Mental State Examination (MMSE) it is an 11-question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. The higher the score suggests less cognitive impairment. A score of 24-30 suggests no cognitive impairment. A score of 18-23 suggests mild cognitive impairment. A score of 0-17 suggests severe cognitive impairment. Patients are evaluable for assessment of QoL after completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period. |
| Response Assessment in Neuro-Oncology (RANO) Measurement Form | Assessed up to 24 months | The Response Assessment in Neuro-Oncology criteria were developed as an objective tool for radiologic assessment of treatment response in high-grade gliomas. Disease progression is defined as ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions (with the absolute increase of at least 1 dimension of at least 5 mm) compared with the smallest tumor measurement obtained either at baseline. Response assessment will be performed for patients completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period. |
Countries
United States
Participant flow
Pre-assignment details
Ten patients were assessed for eligibility in this study. One subject did not meet eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Optune+Pulsed Bevacizumab The subjects will undergo 12 months of planned continuous treatment with Optune. The treatment will begin at week 0 and will be continuous throughout the study. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. If after one cycle on, there is no evidence of a repeat response; bevacizumab will be continued for one more cycle. If after two cycles on, there is no repeat response; bevacizumab will be continued with or without other standard chemotherapy until death. If after at least one cycle on, there is evidence of repeat response, bevacizumab will be discontinued for at least one cycle. In addition, the following will be performed: Bevacizumab will be given, physical examination and quality of life questionnaires will be performed and brain MRI.
Bevacizumab: Bevacizumab will be given at 10mg/kg IV every 2 weeks.
Optune: Optune will be worn continuously for 12 months. Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, perpendicular field directions at a maximal intensity of 707mARMS. There will be no adjustments made to the device by investigators or patients/caregivers.
Brain MRI: Brain MRI will be done at screening and every 8 weeks.
Quality of Life Questionnaires: The quality of life questionnaires will be performed within 14 days of treatment and every 4 weeks. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Optune+Pulsed Bevacizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 54.7 years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 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 | 0 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 | 8 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 9 |
| other Total, other adverse events | 6 / 9 |
| serious Total, serious adverse events | 4 / 9 |
Outcome results
Primary
Overall Survival
Overall survival is defined as time interval from date of starting Optune to date of death or censoring whichever happens first.
Time frame: from date of starting Optune to date of death or censoring, whichever comes first, assessed up to 24 months
Population: participants completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Optune+Pulsed Bevacizumab | Overall Survival | 7.4 months |
p-value: <0.001Log Rank
Secondary
Karnofsky Performance Scale
The Karnofsky Performance Scale is rated from 0 - 100 with 0 = death and 100 = normal without complaints or evidence of disease. A higher score means the patient is better able to carry out daily activities. Patients are evaluable for assessment of QoL after completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
Time frame: Assessed up to 24 months
Population: participants completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Optune+Pulsed Bevacizumab | Karnofsky Performance Scale | 73.3 score on a scale | Standard Deviation 5.8 |
Secondary
Mini-Mental Status Exam
The Mini Mental State Examination (MMSE) it is an 11-question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. The higher the score suggests less cognitive impairment. A score of 24-30 suggests no cognitive impairment. A score of 18-23 suggests mild cognitive impairment. A score of 0-17 suggests severe cognitive impairment. Patients are evaluable for assessment of QoL after completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
Time frame: Assessed up to 24 months
Population: participants completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Optune+Pulsed Bevacizumab | Mini-Mental Status Exam | 23.2 score on a scale | Standard Deviation 5.1 |
Secondary
Response Assessment in Neuro-Oncology (RANO) Measurement Form
The Response Assessment in Neuro-Oncology criteria were developed as an objective tool for radiologic assessment of treatment response in high-grade gliomas. Disease progression is defined as ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions (with the absolute increase of at least 1 dimension of at least 5 mm) compared with the smallest tumor measurement obtained either at baseline. Response assessment will be performed for patients completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
Time frame: Assessed up to 24 months
Population: after completing at least 8 weeks of treatment with the Optune device with compliance rate \> 60% in at least one 4-week period.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Optune+Pulsed Bevacizumab | Response Assessment in Neuro-Oncology (RANO) Measurement Form | Progressive disease | 2 Participants |
| Optune+Pulsed Bevacizumab | Response Assessment in Neuro-Oncology (RANO) Measurement Form | Stable disease | 1 Participants |