Temozolomide, With or Without WSD0922-FU, for the Treatment of EGFR-Mutant, IDH-Wildtype Glioblastoma

Inclusion Criteria:

* Age \>= 18 years
* Histopathologic diagnosis of glioblastoma, IDH-wildtype \[as defined by the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors\] on primary pathology review

  * NOTE: MGMT promoter methylation status must have been performed
* Glioblastomas must have a pathogenic EGFR mutation, with or without EGFR amplification, detected by Clinical Laboratory Improvement Act (CLIA)-certified next-generation sequencing

  * EGFR mutation includes both deoxyribonucleic acid (DNA) sequence variants (e.g. point mutations, etc.) and transcript variants (e.g. EGFRvIII, etc.)
  * EXCEPTIONS: Glioblastomas which are EGFR wildtype with amplification are excluded. Glioblastomas which only have EGFR variants of unknown significance (without any pathogenic EGFR mutations) are also excluded
* Patients must have completed standard radiation (60 Gy in 30 fractions) with concurrent temozolomide (missing no more than 2 weeks of temozolomide), and adequately recovered from treatment related toxicities

  * NOTE: Adjuvant temozolomide must not have been initiated
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Hemoglobin \> 9.0 g/dL (obtained =\< 14 days prior to registration)
* Leukocytes \> 3.0 x 10\^9/L (obtained =\< 14 days prior to registration)
* Absolute neutrophil count (ANC) \> 1.5 x 10\^9/L (obtained =\< 14 days prior to registration)
* Platelet count \> 100 x 10\^9/L (obtained =\< 14 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) (\< 3 x ULN for patients with Gilbert's disease) (obtained =\< 14 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 3 x ULN (obtained =\< 14 days prior to registration)
* Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =\< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =\< 14 days prior to registration)
* Calculated creatinine clearance \>= 45 mL/min using the Cockcroft-Gault formula (obtained =\< 14 days prior to registration)
* Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only
* Provide written informed consent
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* Must be willing to take light-protective measures during the study and for two weeks after last dose of WSD0922-FU
* Willingness to provide mandatory tissue specimens for correlative research

Exclusion Criteria:

* Patients deemed to have progressive disease based on clinical deterioration after chemoradiation or radiographic progression outside of the radiation field

  * EXCEPTION: Patients deemed to have pseudoprogression are eligible; however, this should be controlled on =\< 4 mg of dexamethasone and should not require bevacizumab at study onset
* Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown:

  * Pregnant persons
  * Nursing persons
  * Persons of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception
* Any of the following prior therapies:

  * Surgery for glioblastoma =\< 3 weeks prior to registration
  * Radiation therapy =\< 2 weeks prior to registration
  * Systemic therapies intended for the management of the glioblastoma, including but not limited to:

    * Targeted therapies
    * EGFR inhibitors
    * Alkylating chemotherapy
    * Adjuvant temozolomide (note that temozolomide administered concurrent with radiation is NOT an exclusion criterion)
    * Immunotherapy
    * Biologics
    * Any other systemic therapies \[Food and Drug Administration (FDA) approved, off-label, investigational\]
    * Bevacizumab
  * Non-enzyme-inducing anticonvulsants \< 2 weeks prior to registration
  * Strong inducers and strong inhibitors of CYP3A \< 14 days prior to registration
* Failure to adequately recover from any adverse events or complications related to any of the following therapies received prior to registration:

  * Craniotomy and resection of tumor
  * Stereotactic biopsy of tumor
  * Other major surgical procedure
  * Radiation therapy \< 2 weeks prior to registration
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Examples include (but are not limited to) refractory nausea and vomiting (if not controlled by supportive therapy), inability to swallow the formulated product, previous significant bowel resection, other chronic gastrointestinal diseases, etc
* Uncontrolled intercurrent illness including, but not limited to:

  * Ongoing or active infection
  * Severe skin lesions such as skin/pressure ulcers, chronic leg ulcers or non-healing wounds.
  * Active history of keratitis
  * Symptomatic CNS complications that require urgent neurosurgical or medical (e.g. mannitol) intervention
  * Known intracranial hemorrhage which is unrelated to tumor
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  * Or psychiatric illness/social situations that would limit compliance with study requirements
* Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy

  * NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy within the last 3 years that would interfere with treatment on this protocol

  * EXCEPTIONS: non-melanoma skin cancer, carcinoma in situ of the cervix, patients on hormonal therapy for treated breast or prostate cancer
* History of myocardial infarction =\< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias