Testing the Addition of an Anti-Cancer Drug, Mycophenolate Mofetil, to the Usual Treatment (Radiation Therapy and Temozolomide) for Advanced Brain Cancer

Inclusion Criteria:

* Newly diagnosed primary glioblastoma by World Health Organization (WHO) 2021 criteria
* No spinal cord glioblastoma
* No leptomeningeal disease
* No extracranial metastatic disease
* Patient is a candidate for first-line standard of care chemoradiation per treating physician(s)
* No prior treatment for glioblastoma other than resection (i.e. prior chemotherapy, radiation therapy, or other therapies such as laser ablation are not allowed)
* Prior biopsy and/or resection of glioblastoma must be completed at least 14 days prior to registration with adequate wound healing
* Age ≥ 18 years
* Karnofsky performance status (KPS) ≥ 60
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3
* Platelet count ≥ 100,000 cells/mm\^3
* Hemoglobin (Hg) ≥ 9.0 g/dL
* Calculated (Calc.) creatinine clearance (CrCl) ≥ 25 mL/min

  \* Calculated using the Cockcroft-Gault equation
* Bilirubin ≤ 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3.0 x ULN
* Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.

Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required.

Women and men of reproductive potential must agree to use a highly effective method of birth control throughout their participation in this study and for at least 6 weeks (women) or 90 days (men) after last dose of treatment. Reproductive status and discussions about birth control measures should be documented in the patient's record. Appropriate methods of birth control include, but are not limited to: abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)

* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* No known history of allergic reaction or hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA), or any component of the drug product
* No known history of hypersensitivity reactions to temozolomide (TMZ) or other ingredients in TMZ
* No known medical condition causing an inability to swallow oral formulations of agents
* No active systemic or central nervous system (CNS) infection
* No grade 4 lymphopenia (if absolute lymphocyte count \[ALC\] \< 0.5, then patient must be on prophylaxis for Pneumocystis jirovecii)
* No known history of organ transplantation
* No known hypoxanthine-guanine phosphoribosyl-transferase deficiency
* No known serious intercurrent illness that limits participation in the trial
* No known immunosuppressive condition from autoimmune disease, immune deficiency syndrome, or chronic immunosuppressive therapy
* Patient must be able to undergo MRI brain with and without contrast
* No known phenylketonuria
* No known medical contraindication for mycophenolate mofetil (MMF) per treating physician(s)
* Patients on steroids must be on stable or decreasing dose within 7 days of registration (no more than 8 mg dexamethasone/day or equivalent)

Exclusion Criteria:

\-