The purpose of this study is to determine if the investigational products, DB107-RRV and DB107-FC, as a combination treatment will shrink high-grade glioma (HGG) in patients with recurrent/progressive, resectable or unresectable disease and increase the time that disease is controlled.

Inclusion Criteria:

1. Patients 18-75 years old.
2. Histologically proven HGG that have recurred/progressed (first or second recurrence).
3. Patients with unresectable or resectable HGG (AA or GBM) will be enrolled.
4. Measurable disease on MRI as evidenced by 1 cm on two separate dimensions on MRI fluid attenuated inversion recovery (FLAIR) (non-enhancing) or contrast-enhancement.
5. Last temozolomide dosage 4 weeks prior to surgery.
6. Patients with prior radiation therapy are allowed, but histological tumor diagnosis of recurrent tumor must be confirmed according to the RANO criteria. Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI. If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
7. Presence of Denovo Genomic Marker 7 (DGM7) biomarker in blood.
8. Laboratory values (Platelet count ≥ 80,000, hemoglobin [Hg] ≥10 g/dL, absolute neutrophil count (ANC) > 1,500 cells/mm3, absolute lymphocyte count (ALC) > 500/mm3) and adequate liver function, total bilirubin< 1.5 upper limit of normal (ULN), alanine transaminase (ALT) <2.5 ULN. Estimated glomerular filtration rate (eGFR) should be > 50 mL/min (Cockcroft Gault Formula). Patients with aspartate transaminase (AST) or ALT values >3 ULN and total bilirubin >1.5 mg/dL will be excluded.
9. Patients cannot be pregnant at the time of enrollment or during the study. Patients willing to use one (1) effective method of contraception in addition to barrier methods (condoms) from the time of signing the informed consent form until 12 months after receiving the last dose of DB107-RRV or until there is no evidence of DB107-RRV in their blood, whichever is longer.
10. Karnofsky Performance Score (KPS) ≥ 70.
11. Patient is able to consent and abide by protocol.

Exclusion Criteria:

1. History of active other malignancy (other than non-melanoma skin cancers, cervical ductal carcinoma in situ or localized prostate cancer) within 5 years.
2. Multifocal gliomas that cannot undergo stereotactic biopsy/administration of DB107-RRV will be excluded. Patients with 3 or more intracranial recurrences will be excluded.
3. Histologically confirmed oligodendroglioma or mixed gliomas.
4. History of human immunodeficiency virus (HIV) infection or other forms of severe immunosuppression.
5. Patients with impaired renal function (eGFR<50 cc/min).
6. Patients with bone marrow depression, such as those with a hematological disease or who are being treated with radiation or drugs that depress bone marrow or individuals who have a history of treatment with drugs or radiation that depress bone marrow within 1 month of enrollment.
7. The patient intends to undergo treatment with the Gliadel® wafer at the time of this surgery or has received the Gliadel® wafer < 30 days from surgery.
8. Allergy to 5-FC.
9. Gastrointestinal diseases that prevent absorption of medications such as 5-FC.
10. Pregnancy or patients who are actively breast-feeding.
11. Recent use of cytosine arabinoside (< 3 weeks).
12. Recent treatment with bevacizumamab (< 3 weeks).
13. Recent treatment with temozolomide (<4 weeks).
14. History of bleeding diathesis or current anti-coagulant or anti-platelet usage, including nonsteroidal anti-inflammatory drugs (NSAIDs), at the time of the scheduled resection that cannot be stopped for surgery.
15. Sustained dependence on systemic dexamethasone (>8 mg/day) one month prior to surgery.
16. Severe systemic illnesses including cardiopulmonary dysfunction (New York Heart Association > Grade 2 congestive heart failure (CHF), uncontrolled arrhythmias, significant pulmonary disease > Grade 2 dyspnea) or other serious medical condition or social situations that in the judgement of the Investigator(s) would interfere or limit compliance with study requirements/treatments.
17. The patient has or had any active infection requiring systemic antibiotic, antifungal or antiviral therapy within the past 4 weeks.
18. Current or active coronavirus disease (COVID-19) disease, positive quantitative polymerase chain reaction (qPCR) result.
19. Patients with impaired decision-making capacity.
20. Patients who are currently receiving investigational medications or medical device(s) within 4 weeks (or 5 half-lives of the investigational medication(s), whichever is shorter) prior to enrollment.
21. Patients who have any other disease, either metabolic or psychological, which as per Investigator assessment may affect the patient's compliance or place the patient at higher risk of potential treatment complications.