Chlorpromazine and Standard of Care in Glioblastoma

Inclusion Criteria:

* Patients must have newly diagnosed (i.e., within 5 weeks from recent surgery), histologically or cytologically or molecularly confirmed glioblastoma, gliosarcoma, or diffuse midline glioma.
* Diagnosis must be made by surgical biopsy or excision.
* Therapy must begin ≤ 5 weeks after most recent surgery.
* Age ≥ 18 years
* ECOG performance status 0-2 (Karnofsky \> 50%, see Appendix B).
* A complete blood count and differential must be obtained within 21 days prior to radiation fraction 1, with adequate bone marrow functions as defined below:

  * Absolute neutrophil count (ANC) ≥ 1500 cells per mm\^3
  * Platelets ≥ 100,000 per mm\^3
  * Hemoglobin ≥ 8 g/dL
* Plasma blood chemistries within 21 days of radiation fraction 1, as defined below:

  * Creatinine ≤ 2.0 mg/dL
  * Total bilirubin ≤ 1.5 mg/dL
  * ALT ≤ 3 times the institutional upper limit of normal
  * AST ≤ 3 times the institutional upper limit of normal
* Patient or patient's legally authorized representative's ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

* Recurrent high-grade glioma.
* Significant abnormalities on ECG at screening. QTcF \> 450 msec for males or \> 470 msec for females at screening.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or chlorpromazine.
* Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis, Parkinson's disease, history of myasthenia gravis, or dementia.
* Patients with prior malignancies of the same or different tumor type and patients with concurrent malignancies of the same or different tumor type whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational drug.
* Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma
* Prior radiation therapy to the head or neck, which would result in overlap of radiation therapy fields.
* Patients may not be receiving any other investigational agents. Use of tumor treating fields (TTF) in adjuvant phase is permitted as per standard of care.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, hypoparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements. Uncontrolled seizures despite being on maximal anti-seizure therapy.
* Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide, breastfeeding should be discontinued if the mother is treated with temozolomide.