• 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)

• Absolute neutrophil count (ANC) \>= 1.0 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)

• Platelet count \>= 75 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)

• Total bilirubin =\< 1.5 x upper limit of normal (ULN) or direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 x ULN (within =\< 30 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 x ULN (within =\< 30 days prior to registration)

• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x ULN (within =\< 30 days prior to registration)

• Creatinine or creatinine clearance within normal institutional limits. A creatinine level above the institutional normal limit is acceptable, provided creatinine clearance (CrCl) is \>= 60 mL/min/1.73 m\^2 (within =\< 30 days prior to registration). Creatinine clearance should be calculated using the Cockcroft-Gault formula

• International normalized ratio (INR) =\< 1.5 x ULN or for subjects receiving anticoagulant therapy, INR must be within the therapeutic range of intended use of anticoagulants, as determined by the treating investigator (within =\< 30 days prior to registration)

• Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN or for subjects receiving anticoagulant therapy, aPTT must be within the therapeutic range of intended use of anticoagulants, as determined by the treating investigator (within =\< 30 days prior to registration)

• Willing and able to tolerate brain MRI with contrast. Patients with any known severe allergy to contrast agent(s) should not participate in the study. Patients with mild allergies to contrast agents (e.g., rash only) may participate in the study per treating investigator discretion; it is recommended that these patients be pretreated with acetaminophen and diphenhydramine \[or other institutional standard combination of agent(s) for allergy prep\] prior to injection of the contrast agent

• Willing and able to follow the below contraception requirements:

∙ For Females:

• Female subjects of childbearing potential (defined below) must agree to use adequate contraception (e.g., abstinence or 2 methods of birth control, such as a barrier method in combination with hormonal contraception) starting from the time of informed consent, throughout the duration of treatment with WP1066, and for 2 months after the last dose of WP1066. They also must agree to not donate/freeze eggs during the same timeframe. A female of reproductive potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets both of the following two criteria:

‣ Has not undergone a hysterectomy or bilateral oophorectomy

⁃ Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

∙ For Males:

• Male subjects must agree to use adequate contraception (e.g., abstinence or 2 methods of birth control, such as a barrier method in combination with partner's use of hormonal contraception) starting from the time of informed consent, throughout the duration of treatment with WP1066, and for 4 months after the last dose of WP1066. They also must agree to not donate sperm during the same timeframe Note: The effects of WP1066 on the developing human fetus are unknown. WP1066 could potentially be teratogenic or have abortifacient effects. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

‣ Subject (or subject's legally authorized representative if subject has impaired decision-making capacity) must have the ability to understand and the willingness to sign a written informed consent document

⁃ Both men and women of all races and ethnic groups may participate in this trial