WP1066 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

Inclusion Criteria: * Newly diagnosed, histologically confirmed World Health Organization (WHO) glioblastoma multiforme (GBM), IDH wild-type * External pathology reports are permitted for confirmation of histological diagnosis * Documentation of isocitrate dehydrogenase (IDH) wild-type status will be by IDH1 R123H immunohistochemistry, except for patients =\< age 54 for whom IDH sequencing will be required to detect noncanonical IDH mutations * Documentation of O6-methylguanine-DNA methyltransferase (MGMT) unmethylated status per testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory * Cohort 1 only: Patients with prior gross total resection (GTR) * Cohort 2 only: Patients without prior gross total resection (GTR) * Cohort 2 only: Measurable disease in the brain (per RANO criteria) on brain magnetic resonance imaging (MRI) scan conducted within =\< 4 weeks prior to initiating trial therapy * Cohort 2 only: Patients who would benefit from non-emergent, palliative surgical resection, in the opinion of the local site's tumor board * Able to initiate trial therapy within 8 weeks of the initial brain surgical procedure (biopsy or resection) that lead to the patient's initial diagnosis of GBM * Age \>=18 years * Karnofsky performance scale score \>= 60% * White blood cell (WBC) count \>= 3.0 x 10\^9/L (within =\< 30 days prior to registration) (without growth factor support and/or receipt of blood products within =\< 14 days prior to testing) * A…