Must have received first-line multimodal therapy with surgery followed by temozolomide (unless MGMT promoter unmethylated) and radiation (subjects with GBM must have received temozolomide and radiation concurrently)
Tumor tissue must be available for submission for central pathology review\r\n* Timing requirements:\r\n** If MGMT has been assessed locally by LabCorps or MD Anderson Cancer Center Molecular Diagnostics Lab (MDACC-MDL):\r\n*** Tissue for central pathology review and central MGMT assessment and the official LabCorps or MDACC-MDL MGMT result must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 40\r\n*** The site’s local MGMT report from LabCorp or MDACC-MDL will then be used to stratify the patient; a post-stratification MGMT central review will be performed, but step 2 registration and protocol treatment can proceed without central review of MGMT\r\n*** Patients whose tissue for central pathology review and official LabCorps or MDACC-MDL MGMT result cannot be received by NRG Oncology Biospecimen Bank on or before 40 calendar days after surgery may NOT enroll on this trial\r\n** If MGMT has not been assessed locally by LabCorps or MDACC-MDL:\r\n*** Tissue for central pathology review and central MGMT assessment must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 30\r\n*** Central MGMT analysis will be performed at MDACC-MDL and used for patient stratification; results will be conveyed to NRG Oncology within 10 business days of receipt of the tissue\r\n*** Patients who have not had local MGMT assessment by LabCorps or MDACC-MDL and whose tissue for central pathology review cannot be received by NRG Oncology Biospecimen Bank on or before 30 calendar days after surgery may NOT enroll on this trial\r\n* Tissue Requirements:\r\n** Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; in total, at least 1 cubic centimeter of tissue composed primarily of tumor must be present\r\n** Submission of an accompanying hematoxylin and eosin H&E slide(s) is MANDATORY\r\n** Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy and cavitronic ultrasonic surgical (CUSA) techniques are not allowed
Prior history of temozolomide chemotherapy provided concurrent to external beam radiotherapy and after as per current standard of care; however, temozolomide would not be required to have been provided concomitantly or after radiation if the patient had unmethylated MGMT promoter or if the patient initially was diagnosed with a low grade glioma; at least 8 weeks must have passed from the last dose of temozolomide and first dose of cyclophosphamide and/or rQNestin34.5v.2
Tumor test result shows MGMT methylated or indeterminate tumor subtype
Tumor test result shows MGMT unmethylated type
Tumor MGMT promoter deoxyribonucleic acid (DNA) not methylated (i.e., unmethylated) by central testing
MGMT status known
Pathology must be a GBM, MGMT promoter region determined to be unmethylated and IDH wild type; >= 80% resection of contrast enhanced tumor on post operative MRI is required for randomization, otherwise treatment will occur on the ancillary arm
Patients who have not completed all standard of care treatments, including surgical procedure and radiation therapy (at least 59 Gy)\r\n* If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial\r\n* If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial
Patients must have confirmed GBM MGMT status (tumor must be MGMT promoter unmethylated) by central laboratory Clinical Laboratory Improvement Amendments (CLIA) certified testing at MD Anderson, prior to registration. If initial MGMT testing obtained at an outside institution, MGMT status must be centrally retested at MD Anderson.
Evidence that the tumor MGMT promoter is unmethylated by standard of care assays
Confirmed MGMT-promoter unmethylated status
Histologically proven, newly diagnosed World Health Organization (WHO) grade III or IV astrocytoma that has a methylated MGMT promoter as assessed by the standardized institutional analysis
MGMT promoter methylation testing will be performed by an institutional Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory using a methylation specific polymerase chain reaction (PCR) assay to detect deoxyribonucleic acid (DNA) methylation within the promoter region of the MGMT gene\r\n* Participants with an MGMT promoter that is unmethylated will be enrolled to cohort 1a, while those with tumor MGMT promoter that is methylated, partially methylated, indeterminate or unknown will be enrolled to cohort 1b
ADDITIONAL CRITERIA FOR COHORTS 1A AND 1B PARTICIPANTS ONLY: Cohort 1a: MGMT promoter unmethylated
ADDITIONAL CRITERIA FOR COHORTS 1A AND 1B PARTICIPANTS ONLY: Cohort 1b: MGMT promoter methylated, partially methylated, indeterminate or unknown
Patients who have had a local MGMT testing that is unmethylated are not allowed to participate
Tumor MGMT promoter hypermethylation determined by central testing at MD Anderson
Patient must agree to testing of GBM tumor promoter methylation status of the MGMT gene and tumor (IDH1) gene mutation status. Tissue may be tested at study entry, if not done previously, or data may be obtained from last known test result for MGMT and IDH1. IDH1 status may be assessed at study entry, but MGMT status is required prior to randomization.
First diagnosis of unmethylated MGMT GBM (Cohort 1d and Cohort 1c Part B only)
Patients who have not recovered from the toxic effects of prior chemotherapy and/or radiation therapy will be excluded; guidelines for this recovery period are dependent upon the specific therapeutic agent being used:\r\n* Patients may not have received chemotherapy or bevacizumab =< 4 weeks (except for nitrosourea [6 weeks] or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide [1 week]) prior to starting the study drug unless patients have recovered from side effects of such therapy\r\n* Patients may not have received immunotherapy =< 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy\r\n* Patients may not be less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation\r\n* Patients must have completed all standard of care treatments, including surgical procedure, and radiation therapy (at least 59 Gy)\r\n** If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial\r\n** If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter status is unknown at the time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial
MGMT promoter methylation analysis of surgically resected tumor or tumor biopsy must demonstrate an unmethylated or hypomethylated MGMT promoter status
Methylated or hypermethylated MGMT promoter status within tumor tissue
Histologically proven primary diagnosis of GBM with unmethylated O6-methylguanine-DNA methyltransferase (MGMT).