• Patient must be age \>= 18 years

• Patient has a Karnofsky performance status of \>= 70%

• Patient has a life expectancy of \>= 3 months

‣ When determining the maximum tolerated number of treatment cycles (MTC): patient has a histologically confirmed diagnosis of a grade 3 or 4 glioma (eg., glioblastoma, grade 4 astrocytoma, grade 3 astrocytoma, grade 3 oligodendroglioma). (This part of the study has been completed).

⁃ When enrolling to Treatment Schedules 4 and 4a: patient has glioblastoma at first recurrence.

• Imaging studies show evidence of recurrent, supratentorial tumor(s).

• Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide

• The patient must be in need of surgery for tumor resection

• Based on the neurosurgeon's judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles

• Absolute neutrophil count (ANC) of \>= 1000 cells/mm\^3

• Platelet count \>= 100,000 cells/mm\^3

• Total bilirubin =\< 2.0 mg/dl

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 4 times the institutional upper limit of normal

• Serum creatinine =\< the institutional upper limit of normal

• At least 2 weeks from taking the last dose of a targeted agent

• At least 4 weeks from the last dose of bevacizumab For temozolomide, an interval of 23 days is required from the last dose administered if the patient was recently treated with adjuvant temozolomide, consisting of temozolomide daily for 5 days, repeated every 28 days.

• At least 2 weeks from taking the last dose of a targeted agent.

• At least 4 weeks from the last dose of bevacizumab.

• All significant toxicities from previous anticancer therapy must have stabilized to a new baseline or resolved.

• All participants must have the ability to understand and the willingness to sign a written informed consent.

• The effects of this treatment on a developing fetus are unknown. Therefore, female patients of childbearing potential and sexually-active male patients or who are able to impregnate their partner, must agree to use an effective method of contraception while participating in this study. Patients of childbearing potential must have a negative pregnancy test =\< 2 week prior to registration.