This clinical trial evaluates adding ferumoxytol and pharamcologic ascorbate (vitamin C) to standard of care treatment of glioblastoma multiforme (a type of brain tumor) in adults. All subjects will receive ferumoxytol and pharmacologic ascorbate in addition to the standard treatment.

The initial, standard treatment for glioblastoma multiforme (GBM) involves maximum safe surgical resection followed by radiation combined with temozolomide (a chemotherapy pill you take by mouth).

Participants in this trial will:

• receive intravenous (IV) ferumoxytol the day before starting radiation, then around radiation treatments 6, 25, and 31.
• receive high doses of intravenous (IV) ascorbate three times a week during the combined radiation and chemotherapy phase.
• provide feedback about how they feel and their quality of life. This is done through short surveys as well as discussing with the study team.

Inclusion Criteria:

• Willingness and ability to provide informed consent consistent with Good Clinical Practice (i.e., legally authorized representative will not be used / allowed for this study).
• Stated willingness to comply with all study procedures for the duration of the study
• Aged 18 years or older.
• Newly diagnosed (i.e., within 6 weeks), histologically or molecularly confirmed glioblastoma or diffuse midline glioma.
• Therapy to begin within 6 weeks of last surgery
• Able to take oral medication
• ECOG performance status of 0, 1, or 2 (KPS of >50)
• Recommended to receive temozolomide and radiation therapy
• Medically fit, as determined by the prescribing oncologists, to undergo temozolomide and radiation therapy.
• Agree to use of highly effective contraception from screening until at least 90 days after the last study treatment (study participant should not discontinue contraception until discussing with their treating oncologist(s)).
• Not have significant co-morbid central nervous system disease, such as multiple sclerosis.
• Agree to Lifestyle Considerations throughout study duration

Exclusion Criteria:

• Current use of the following drugs and cannot have a drug substitution or decline the drug substitution: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide. Pharmacologic ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs.
• Current use of antiretroviral drugs (e.g., nelfinavir, abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine). Pharmacologic ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs.
• Insulin requirement
• Requires blood glucose monitoring using finger-stick glucose checks.
• Medical requirement or indication for iron supplementation (including ferumoxytol, ferrous gluconate, ferrous fumarate, or ferrous sulfate). NOTE: Over the counter, patient-elective supplementation is acceptable.
• Inability to undergo MR imaging.
• Pregnancy or lactation (note: potential participants should not engage in 'pump & dump' strategy; lactation must be discontinued).
• Known allergic reactions to ferumoxytol.
• History of Steven's Johnson Syndrome
• History of hemochromatosis.
• Prior radiation treatment that would result in field overlap. For potential participants who have undergone nuclear medicine therapy, including PRRT, the study's radiation oncologist must approve study entry.
• G6PD (glucose-6-phosphate dehydrogenase) deficiency
• Platelet count < 100,000 /mm3 within 21 days of first treatment
• Creatinine ≥ 1.5x the institutional upper limit of normal within 21 days of the first treatment or if creatinine is elevated a creatinine clearance of < 60 mL/(min 1.73 m2)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (requiring inpatient admission or a delay to start of therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Treatment with another investigational drug within 30 days prior to study treatment day 1. Imaging trials (including investigational PET or NM tracers) as well as observational trials are acceptable.
• Clinical trials with an endpoint of treating the patient's cancer, including behavioral, nutritional and/or device human subject studies.

Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.

Study protocol and informed consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting.

An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers.