Description:
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.
Title
- Brief Title: TTFields and Pulsed Bevacizumab for Recurrent Glioblastoma
- Official Title: A Phase 2, Multi-center, Single Arm, Histologically Controlled Study Testing the Combination of TTFields and Pulsed Bevacizumab Treatment in Patients With Bevacizumab-refractory Recurrent Glioblastoma
Clinical Trial IDs
- ORG STUDY ID:
IRB201600074
- SECONDARY ID:
OCR14874
- NCT ID:
NCT02663271
Conditions
- Glioblastoma Multiforme
- Glioblastoma
- Malignant Glioma
- GBM
Interventions
| Drug | Synonyms | Arms |
|---|
| Bevacizumab | Avastin | Historical Controls |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Optune+Pulsed Bevacizumab | Experimental | 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. | |
| Historical Controls | Other | Historical controls treated with continuous bevacizumab alone or in combination with standard chemotherapy will be compared with the Optune arm. Information will be collected: Bevacizumab or additional chemotherapy, physical examination and quality of life questionnaires performed and brain MRI. | |
Eligibility Criteria
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 22 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-free survival between the groups |
| Time Frame: | Assessed up to 24 months |
| Safety Issue: | |
| Description: | Survival times in both the historical control group and the experimental group are assumed to follow Weibull distributions. Weibull-distributed survival times, the hazard ratio (experimental vs control) is equal to the ratio of the control group median survival time (m1) to the experimental group median survival time (m2), raised to the power of the shape parameter k: HR = (m1/m2)k |
Secondary Outcome Measures
| Measure: | Number of adverse events |
| Time Frame: | Change from baseline and every month up to 24 months |
| Safety Issue: | |
| Description: | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting for grade 3 or higher. |
| Measure: | Karnofsky Performance Scale |
| Time Frame: | Change from baseline and every month up to 24 months |
| Safety Issue: | |
| Description: | The Karnofsky Performance Scale is rated from 0 - 100 with 0 = death and 100 = normal without complaints or evidence of disease. |
| Measure: | Mini-Mental Status Exam |
| Time Frame: | Change from baseline and every month up to 24 months |
| Safety Issue: | |
| Description: | |
| Measure: | Response Assessment in Neuro-Oncology (RANO) Measurement Form |
| Time Frame: | Change from baseline and every 2 months up to 24 months |
| Safety Issue: | |
| Description: | Measurable lesions from the brain MRI must be contrast enhancing, have a minimum size of two perpendicular diameters > 10mm, no cavity or cyst in measurement. In addition, non-measurable lesions include lesions that are too small (<10 x 10mm), lesions that do not enhance, and lesions with a poorly defined margin. The lesions are measured with the sum of products of diameters (SPD). |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | University of Florida |
Last Updated
August 11, 2021
