Inclusion Criteria

1. Last dose of chemotherapy: At least 4 weeks
2. Patient must willingly provide written consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
3. Patients must be ≥ 18 years old.
4. Patients must have histologically confirmed initial diagnosis of primary intracranial World Health Organization (WHO) Grade IV malignant glioma (glioblastoma, GBM), now recurrent. Patients with recurrent disease whose initial diagnostic pathology confirmed glioblastoma will not need re-biopsy. Alternately, patients with prior intracranial low-grade glioma or anaplastic glioma will be eligible, if histologic assessment demonstrates transformation to GBM (first diagnosis of secondary GBM).
5. Patients must have radiographic evidence of recurrent/progressive GBM after prior therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Histologically documented transformation from a lower grade gliomas will be considered first recurrence.
6. 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.
7. Patients must have Karnofsky Performance Status (KPS) 70 or higher.
8. Patients must have been previously treated for GBM with radiation with concurrent and adjuvant temozolomide chemotherapy.
9. Adequate recovery from all recent surgery is required. At least 21-days must have elapsed from the time of any major surgery, including craniotomy/tumor resection. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
10. Patients must ≥ 12 weeks from radiotherapy, to minimize the potential for magnetic resonance imaging (MRI) changes related to treatment (pseudo progression) that might be misdiagnosed as true progression of disease, unless the patient fulfills criteria for early progressive disease by RANO.
11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks must have elapsed from the time of treatment, and the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
12. Patients must be at least 4 weeks from last dose of chemotherapy.
13. Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last dose of prior investigational anti-cancer drugs.
14. Patients must have recovered from all treatment-related toxicities to Grade 1 or less.
15. If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for ≥ 5 days prior to baseline MRI.
16. Patients must have a predicted life expectancy of at least 12 weeks.
17. Patients must have adequate bone marrow and organ function.
18. Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and accessible for follow-up.
19. If the patient has been using the Optune™ device, it will be discontinued before initiating treatment with either study medication, and per inclusion criterion listed above, the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
20. Pregnancy restrictions - Women of childbearing potential must have a negative B-HCG documented within 7 days prior to registration