A Phase I Study to Investigate the Safety, Pharmacokinetic Profile and the Efficacy of EDO-S101, a First-in-Class Alkylating HDACi Fusion Molecule in Patients With Newly Di-Agnosed MGMT-Promoter Unmethylated Glioblastoma

• Be willing and able to provide written informed consent for the trial.

• Have histologically confirmed World Health Organization grade IV glioma (glioblastoma \[GB\] or gliosarcoma).

• Patients must have preliminary glioblastoma (GBM) MGMT status (tumor must be MGMT promoter unmethylated) determined prior to study entry. If initial MGMT status is determined to be unmethylated, by an outside institution the patient may be enrolled and begin treatment. However, MGMT status must be retested following enrollment by central laboratory Clinical Laboratory Improvement Act (CLIA) certified testing at MD Anderson, if tissue is available. Confirmed IDH wildtype. The presence of an IDH mutation will be an exclusionary criteria for trial enrollment.

• Have a performance status of \>= 60 on the Karnofsky performance scale (KPS).

• If patient is on steroids, patient must be on a stable or decreasing dose of steroids for at least 5 days at the time of baseline brain magnetic resonance imaging (MRI).

• Absolute neutrophil count (ANC) \>= 1,500 /mcL (within 14 days \[+3 working days\] of treatment initiation).

• Platelets \>= 100,000 /mcL (within 14 days \[+3 working days\] of treatment initiation).

• Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L (within 14 days \[+3 working days\] of treatment initiation).

• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) =\< 1.5 x upper limit of normal (ULN) OR \>= 60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN (within 14 days \[+3 working days\] of treatment initiation).

• Serum total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN (within 14 days \[+3 working days\] of treatment initiation).

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN (within 14 days \[+3 working days\] of treatment initiation).

• International normalized ratio (INR) or prothrombin time (PT), activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (within 14 days \[+3 working days\] of treatment initiation).

• Female subjects of childbearing potential should have a negative serum pregnancy test within 72 hours of starting first dose of study drug.

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the duration of the study. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

• Male subjects should agree to use an adequate method of contraception during the course of the study.

• Patients must have completed standard radiation therapy with concurrent TMZ and must not have evidence of progressive disease on post treatment imaging. Progression can only be defined using diagnostic imaging if there is new enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line) or if there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas \[i.e, \> 70% tumor cell nuclei in areas\], high or progressive increase in MIB-1 proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor). Note: Given the difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in the absence of radiographic or histologic confirmation of progression, will not be sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent chemoradiotherapy. (For Stage 1: post-chemoradiation group only)

• Prescribed treatment with concomitant temozolomide must be consistent with the Food and Drug Administration (FDA) package insert. The dose must be 75 mg/m\^2 daily for the 6 to 6.5 weeks of radiation therapy. If the patient missed more than 1 week of temozolomide dosing during radiotherapy, then they are not eligible for the trial. EDO-S101 can accentuate thrombocytopenia induced by temozolomide. Therefore, if patients had a platelet \< 75,000/mm\^3 during concomitant temozolomide therapy during radiation, they are not eligible for this trial

⁃ NOTE: Complete blood count (CBC) should be monitored during chemoradiation and lowest platelet count must be submitted at registration. (For stage 1: post-chemoradiation group only)

• Patients must have undergone surgery of their GBM, and must not have had any further treatment following surgery. A minimal interval of 7 days between the day of surgery and the day of inclusion should be respected; a maximal interval of 31 days between the day of surgery and the day of inclusion should be respected; the patient should have fully clinically recovered from the surgery. (For stage 2: radiation with concurrent and adjuvant EDO-S101 only)

• Patients must undergo surgery and must not have further treatment. (For MTD expansion cohort only)