• Arms A-D: Prior resection of histologically diagnosed high-grade gliomas (III and IV) defined as participants who have progressed on or following standard therapy as determined by the investigator. Arm E: Participant at first recurrence with an unmethylated HGG, has completed standard therapy and is not currently scheduled for resection.

• Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI with positive perfusion.

• Arms A-D (only): Have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with a volume of at least 6 cm3 and ≤ 20cm3 of targeted treatment area.

• Age ≥18 at time of consent.

• Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982).

• Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility)

• Adequate bone marrow function:

⁃ absolute neutrophil count ≥1,000/mcL

⁃ Platelets (at time of surgery) ≥100,000/mcL

⁃ hemoglobin ≥8.0 g/dL Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator.

• Adequate hepatic and renal function:

⁃ total bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.

⁃ AST(SGOT) ≤3 X institutional ULN

⁃ ALT(SGPT) ≤3 X institutional ULN

⁃ GGT ≤3 X institutional ULN

⁃ Serum creatinine ≤1.5 X institutional ULN

• Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant has had a hysterectomy.

• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 3 months after the end of treatment administration.

• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner and for an additional 1 month after the end of treatment administration. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid.

⁃ Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A washout period of at least 14 days is required between last chemotherapy dose and Day 1 (provided the patient did not receive radiotherapy).

⁃ Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and Day 1.

⁃ Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable).

⁃ Has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.

⁃ Willingness and ability to comply with scheduled visits, treatment plans, Lifestyle Considerations, laboratory tests and other procedures.