DB107-RRV, DB107-FC, and Radiation Therapy With or Without Temozolomide (TMZ) for High Grade Glioma

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be eligible for study entry:

1. Participant has provided written informed consent.
2. Participant is between 18 years of age and 75 years of age, inclusive.
3. Participant must have a Karnofsky Performance Scale (KPS) of \>= 70.
4. Participant must have newly diagnosed adult-type diffuse gliomas (World Health Organization Classification 2021) that has not been previously treated with surgery, radiation or chemotherapy (specifically astrocytoma, Isocitrate dehydrogenase (IDH)-mutant or glioblastoma, IDH-wildtype).
5. Based on the pre-operative evaluation by neurosurgeon, participant is a candidate for \>= 80% resection of the enhancing region.
6. The primary tumor must be made available for central testing for IDH1 mutation, O6-methylguanine-DNA methyl-transferase (MGMT) methylation status.
7. Willing to provide a blood sample to determine Denovo Genomic Marker 7 (DGM7) status.
8. Laboratory values adequate for patient to undergo surgery, including:

   1. Platelet count \>= 60,000/mm\^3
   2. Hemoglobin \>= 10 g/dL
   3. Absolute neutrophil count (ANC) \>= 1,500/mm\^3
   4. Absolute lymphocyte count \>= 500/mm\^3
   5. Total bilirubin \<=1.5 x upper limit of normal (ULN) (unless patient had Gilbert's syndrome)
   6. alanine aminotransferase (ALT) \<= 2.5 x ULN
   7. Estimated glomerular filtration rate of at least 50 mL/min by Cockcroft Gault Formula
9. Female participants of child-bearing potential and male participants must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30-days prior to the first administration of study drug, for the duration of study participation, and for 90-days following completion of the therapy. Should a female participant become pregnant or suspect a pregnancy while participating in this study, the treating physician must be informed immediately. IF a male participant impregnates or is suspected of impregnating a woman while participating in this study, the treating physician must be informed immediately.

   • A female of child-bearing potential is any women (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
   * Has not undergone a hysterectomy or bilateral oophorectomy or
   * Has not had \>= 12 months of non-therapy-induced amenorrhea.
10. Participants must not be breastfeeding.
11. Participants must have the ability to understand, and the willingness to comply with the scheduled visits, treatment schedule, laboratory testing and other requirements of the study.

Exclusion Criteria:

Participants may not meet any of the following exclusion criteria to be eligible for study entry:

1. Prior treatment for High Grade Glioma (HGG).
2. History of other malignancy unless the participant has been disease-free for at least 5 years. Adequately treated basal cell carcinoma or squamous cell skin cancer is not exclusionary regardless of time, as well as localized prostate carcinoma or cervical carcinoma in situ after curative treatment.
3. Histological confirmed oligodendroglioma (IDH-mutant and 1p.19q-codeleted) or mixed glioma.
4. A contrast-enhancing brain tumor that is any of the following:

   1. Multi-focal (defined as 2 separate areas of presumed tumor whether contrast enhancing or not, measuring at least 1cm in 2 planes that are not contiguous
   2. Associated with either diffuse subependymal or leptomeningeal dissemination or
   3. \> 5cm in any dimension.
5. Participant has or had an active infection requiring antibiotic, antifungal or antiviral therapy in the 4 weeks preceding study Cycle 1: Day 1.
6. Participant has any bleeding diathesis, or must take anticoagulants, or antiplatelet agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), at the time of the scheduled resection that cannot be interrupted for surgery.
7. Participant is HIV positive.
8. Participant has Hepatitis B (positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and positive test for hepatitis B Virus (HBV) DNA) or Hepatitis C (positive tests for hepatitis C Virus (HCV) Antibody and HCV-RNA) or Hepatitis B and C co-infection (positive test for HBsAg or HBcAb and positive test for HCV Antibody).
9. Participant has a history of allergy or intolerance to flucytosine (DB107-FC).
10. Participant has a gastrointestinal disease that would, in the opinion of the Investigator, prevent him or her from being able to swallow or absorb flucytosine.
11. Participant intends to undergo treatment with the Gliadel® wafer at the time of resection surgery or has received Gliadel® wafer \< 30 days from Cycle 1: Day 1.
12. Severe pulmonary, cardiac or other systemic disease, which as per Investigator assessment would prevent surgical resection.
13. Participant who have any other disease or condition, which as per Investigator assessment may affect the participant's compliance or place the participant at higher risk of potential treatment complications.