Intensified Hypofractionated Radiation Therapy Using MR-Linac with Temozolomide for the Treatment of Glioblastoma

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)
• Patient must provide informed consent prior to surgery if FastGlioma assessment is planned. FastGlioma is not a requirement to enroll onto the study
• Ability to undergo radiotherapy with an MR-Linac machine including effective immobilization for the duration of treatment and required MR sequences
• Hemoglobin >/= 9.0 g/dL
• Absolute neutrophil count >/= 1.5 x 10^9/L
• Platelet count >/= 100 x 10^9/L
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 x upper limit of normal (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. We ask patient to practice contraception for at least 6 months after radiation therapy (RT). Highly effective methods of contraception are those methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: ** intrauterine device (IUD) ** bilateral tubal occlusion ** vasectomized partner ** sexual abstinence (i.e., refraining from heterosexual intercourse during the study treatment and 6 months after the last dose of study treatment). * Unacceptable contraception methods ** Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not acceptable methods of contraception. Female condom and male condom should not be used together

Exclusion Criteria

• Patients with limited capacity to consent at enrollment
• Uncontrolled intercurrent illness, including, but not limited to: * Ongoing or active infection including but not limited to the below. Patients on prophylactic antibiotics may be eligible after discussion with the study principal investigator (PI). ** Tuberculosis (tuberculosis testing by local institutional practice is required prior to receipt of chemoimmunotherapy) ** Hepatitis B (HBV) defined as presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B virus core antibody (anti-HBcAb) with detectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA) ≥10 IU/mL (testing is required prior to receipt of chemoimmunotherapy). *** Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and the absence of HBsAg) are eligible. ** Hepatitis C (HCV) defined as positive HCV antibody (testing is required prior to receipt of chemoimmunotherapy). *** Patients positive for hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid (RNA). ** Uncontrolled HIV/AIDS. Testing for HIV 1/2 antibodies is required prior to receipt of chemoimmunotherapy. Patients with known HIV are allowed on study provided they have: *** A stable regimen of highly active anti-retroviral therapy (HAART) *** No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infection *** A CD4 count > 250 cells/mcL *** An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based testing * Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, myocardial infarction (MI)/transient ischemic attack (TIA)/cerebrovascular accident (CVA) within 3 months prior to study enrollment, uncontrolled cardiac arrhythmia. Patients with cardiac pacemakers will not be able to participate. * Active interstitial lung disease (ILD) or history of immune-mediated pneumonitis. * Active primary immunodeficiency. * Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent
• Other co-morbid disease or conditions that would cause undue risk and/or interfere with the conduct or interpretation of the trial in the opinion of the treating investigator
• 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 National Cancer Institute (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 immunohistochemistry (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 </= 30 days prior to planned procedure date
• Contraindications to MRI examination as per standard MRI screening policy
• Contraindication to Gadolinium-based contrast media
• Inability to lie flat in a supine position for at least 30 minutes
• Inability to tolerate immobilization in a head thermoplastic mask
• Prior therapeutic cranial irradiation
• Leptomeningeal dissemination of disease
• Patients with any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol