• Signed and dated informed consent.

• Male or female participants aged ≥ 12 years on the day of signing informed consent.

• Has histologically confirmed supratentorial World Health Organization grade 4 recurrent astrocytoma to include recurrent glioblastoma (IDH-wildtype grade 4 astrocytoma) recurrent IDH-mutant grade 4 astrocytoma, and recurrent gliosarcoma with any prior number of recurrences, and who have received prior radiation and temozolomide therapy. Participants will be eligible if the original histology was lower-grade glioma grade 2 or 3 and a subsequent histological diagnosis of recurrent glioblastoma or IDH-mutant grade 4 astrocytoma is made.

• Karnofsky Performance Score (KPS) of \>70 at trial entry. Lansky \>70 at trial entry for patients less than 16.

• Must be at least 12 weeks from receiving conformal radiation, unless RANO criteria for early progression are met.

• A baseline brain MRI with Advance Brain Tumor Imaging (ABTI) must be obtained no more than 30 days prior to study registration

• Patients having undergone recent surgery are eligible so long as they are at least 3 weeks from resection or at least 1 week from stereotactic biopsy and recovered from any operative or perioperative complications. Patients with non-measurable tumor after resection will NOT be excluded; if they do not experience tumor progression while on trial, response will be labeled as stable disease (and not as complete response).

• Adequate hematological function defined by white blood cell (WBC) count ≥ 3 x 10°9/L with absolute neutrophil count (ANC) ≥ 1.5 x 10°9/L, lymphocyte count ≥ 0.5 x 10°9/L, platelet count

• ≥ 100 x 10°/L, and Hgb ≥ 9 g/ dL (in absence of blood transfusion).

• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 x ULN, an AST level ≤ 2.5 x ULN, and an ALT level ≤ 2.5 x ULN, and INR ≤ 1.5

⁃ Adequate renal function defined creatinine ≥ 1.5 X upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min for participant with creatinine levels \> 1.5 X institutional ULN

⁃ Female participant of childbearing potential should have a negative serum pregnancy test within 14 days (+/-2 working days) of study registration.

⁃ Female participants of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study and for 3 months after the last dose of study therapy. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

⁃ Male participants should agree to use 2 methods of highly effective contraception starting with the first dose of study therapy and for 3 months after the last dose of study therapy.

⁃ For the surgical expansion group (Group 2): there must be at least 1 cm2 of contrast-enhancing disease that is considered resectable by the neurosurgeon.