This is a phase 1 study to examine the safety and tolerability of biology-guided dose intensified hypofractionated radiation therapy (RT) using MR-Linac for patients with high grade glioma (HGG). Investigators will enroll 20 patients with Grade 3 or 4, IDH wild-type (IDHwt), HGG. Intraoperative assessment of residual tumor burden will be performed at 6 surgical margins (anterior, posterior, superior, inferior, medial, lateral) using FastGlioma. Each margin will be graded on a scale of 0 to 3, with 0 being no tumor, 1 atypical cell, 2 sparse tumor infiltration, and 3 dense tumor infiltration.

Inclusion Criteria:

• Participants male or female of age 18 or older
• Ability to understand and the willingness to sign a written informed consent document
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
• Have histologically confirmed, newly diagnosed high grade glioma (histologic grade 3 or 4, IDH wildtype)
• Must have completed surgery with FastGlioma
• Patients can either be consented before or after surgery. Patients can be a maximum of 6 weeks post-surgery period to the start of MRL-RT.
• Ability to undergo radiotherapy with an MR-Linac machine including effective immobilization for the duration of treatment and required MR sequences
• Subjects must have adequate bone marrow, liver and kidney function defined as:
• Hemoglobin >/= 9.0 g/dL
• Absolute neutrophil count >/= 1.5 x 109/L
• Platelet count >/= 100 x 109/L
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 x ULN
• Creatinine within normal limits OR measured creatinine clearance (CL) >50 mL/min OR calculated creatinine clearance (CL) >50 mL/min as determined by Cockcroft-Gault
• Men who partner with a woman of childbearing potential must agree to use effective, dual contraceptive methods (i.e., a condom, with female partner using oral, injectable or barrier method) while on study and for 4 months afterward.
• For Female participants:
• While on study treatment a participant must not breastfeed or be pregnant
• Have a negative highly sensitive (eg, beta-human chorionic gonadotropin [β-hCG]) pregnancy test at screening and agree to further pregnancy tests per the protocol.
• Practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.
• Female participants (pre- or perimenopausal) must use the appropriate highly effective, contraception method within 28 days of the first dose of study treatment.

Exclusion Criteria:

• Uncontrolled intercurrent illness
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessments of the investigational regimen. Patients whose prior or concurrent malignancy natural history and/or treatment does NOT have the potential to impact safety or study assessments are eligible.
• Any unresolved toxicity NCI Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥2 from a previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included after consultation with the study PI.
• Prior evidence of IDH mutation by IHC or DNA sequencing (i.e., IDH wild type only)
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Subject is pregnant or planning to become pregnant or nursing (lactating).
• Subject is enrolled in another investigational trial and/or is taking investigational medication and/or has been treated with an investigational device \

The de-identified participant data from the final research dataset will be shared upon reasonable request beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: Jonathan.Yang@nyulangone.org. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The investigator who proposed to use the data will be granted access upon reasonable request. Requests should be directed to Jonathan.Yang@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.