Dexamethasone and Azeliragon for Management of Post-Resection Cerebral Edema in Patients with Glioblastoma

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative
* Age: \>= 18 years
* Karnofsky performance status of \>= 60%
* Histologically confirmed glioblastoma or radiographic findings consistent with a high grade glioma in patients undergoing surgery for initial diagnosis
* If midline shift is present on the pre-op brain MRI, it must be less than 10 mm
* The patient is planning to undergo a standard of care craniotomy, and the neurosurgeon anticipates being able to perform a gross total resection of tumor
* If a patient is taking more than 3 mg twice daily (bid) of dexamethasone at the time of signing the consent form, it is anticipated by the neurosurgeon that the participant will be able to decrease their dose of dexamethasone to 3 mg bid by 6 days before the surgery

  * Note: If the patient is not able to decrease their dose of dexamethasone to 3 mg BID 6 days before surgery, then the patient will not be allowed to participate in the study
* The patient is not planning to participate in another clinical trial during the study period
* The patient has recovered from any acute toxic effects (except alopecia) to =\< grade 1 of prior anti-cancer therapy
* Absolute neutrophil count (ANC) \>= 1,000/mm\^3
* Platelets \>= 100,000/mm\^3
* Total bilirubin =\< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease)
* Aspartate aminotransferase (AST) =\< 1.5 x ULN
* Alanine aminotransferase (ALT) =\< 1.5 x ULN
* Creatinine clearance of \>= 60 mL/min by the Cockcroft-Gault formula
* International normalized ratio (INR) OR prothrombin (PT) =\< 1.5 x ULN
* Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN
* Corrected QT (QTc) =\< 480 ms

  * Note: To be performed within 28 days prior to day 1 of protocol therapy
* People of childbearing potential: negative urine or serum pregnancy test
* Agreement by people of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (regardless of gender) or not being free from menses for \> 1 year (people with uteri only)

Exclusion Criteria:

* Less than 6 weeks since taking a nitrosourea-containing chemotherapy regimen; less than 4 weeks since completing a non-nitrosourea-containing cytotoxic chemotherapy regimen (except temozolomide: only patients with an interval of less than 23 days from the last dose administered when treated with the temozolomide regimen of daily for 5 days, repeated every 28 days are excluded); less than 2 weeks from taking the last dose of a targeted agent; less than 4 weeks from the last dose of bevacizumab
* Less than 3 months since focal brain radiation unless recurrent disease has been confirmed surgically or the area of recurrent tumor is outside of the radiation field
* The patient is taking a medication that is a strong CYP3A4 inducers/ inhibitors within 14 days prior to day -6 of protocol therapy
* The patient is unwilling to stop taking herbal medications prior to the start of study treatment
* The patient is taking a hepatic enzyme-inducing anticonvulsant within 14 days prior to day -6 of protocol therapy
* Clinically significant uncontrolled illness
* Active infection requiring antibiotics
* Human immunodeficiency virus (HIV)-positive
* Undergoing treatment for another cancer
* Issues with tolerating oral medication (e.g. inability to swallow pills, malabsorption issues, ongoing nausea or vomiting)
* Chronic or active viral infection of the central nervous system (CNS)
* Pregnant or breastfeeding
* Coagulopathy or bleeding disorder
* Inability to undergo a brain MRI
* Inability to tolerate dexamethasone
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)