Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION:

• No known IDH mutation. (If tested before step 1 registration, patients known to haveIDH mutation in the tumor on local or other testing are ineligible and should not beregistered)

• Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block andhematoxylin & eosin (H&E) stained slide to be sent for central pathology review forconfirmation of histology and MGMT promoter methylation status. Note that tissue forcentral pathology review and central MGMT assessment must be received by the NewYork University (NYU) Center for Biospecimen Research and Development (CBRD) on orbefore postoperative calendar day 23. If tissue cannot be received by postoperativecalendar day 23, then patients may NOT enroll on this trial as central pathologyreview will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMTanalysis will generally be conveyed to NRG Oncology within 10 business days ofreceipt of tissue. Note: In the event of an additional tumor resection(s), tissuemust be received within 23 days of the most recent resection and the latestresection must have been performed within 30 days after the initial resection.Surgical resection (partial or complete) is required; a limited biopsy is notallowed because it will not provide sufficient tissue for MGMT analysis

• Note: The central pathology review and central MGMT results determineeligibility. Therefore, patients may be offered the opportunity to consentREGARDLESS of local pathology and MGMT results, and consent can occur BEFORElocal pathology interpretation is finalized and BEFORE local MGMT testing isconducted

• Contrast-enhanced brain MRI within 3 days after surgery

• MRI with Axial T2 weighted FLAIR {preferred} or T2 turbo spin echo (TSE)/fastspin echo (FSE) and 3-dimensional (3D) contrast-enhanced T1 sequences arerequired

• 3D pre contrast-enhanced T1 sequences are strongly suggested

• Women of childbearing potential (WOCBP) and men who are sexually active with WOCBPmust be willing to use an adequate method of contraception hormonal or barriermethod of birth control; or abstinence during and after treatment

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry

• PRIOR TO STEP 2 REGISTRATION:

• Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype ofglioblastoma) confirmed by central pathology review

• Note: diagnoses of "Molecular glioblastoma" per the Consortium to InformMolecular and Practical Approaches to Central Nervous System (CNS) TumorTaxonomy (c-IMPACT-NOW) criteria or "CNS grade 4" per the World HealthOrganization (WHO) 2021 criteria are NOT relevant

• MGMT promoter without methylation confirmed by central pathology review. Note:Patients with tissue that is insufficient or inadequate for analysis, fails MGMTtesting, or has indeterminate or methylated MGMT promoter are excluded.

• Note: central pathology review and central MGMT results determine eligibility;local pathology or MGMT results cannot be used for eligibility/randomization

• Note: patients with methylated MGMT may be considered for enrollment onNRG-BN011

• IDH mutation testing by at least one method (such as immunohistochemistry for IDH1R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligibleand must be registered as ineligible at step 2.)

• Note: this test is not being performed in real time as part of central reviewand will not be provided to sites from a centrally performed test

• History/physical examination within 28 days prior to step 2 registration

• Karnofsky Performance Status (KPS) >= 70 within 28 days prior to step 2 registration

• Neurologic function assessment within 28 days prior to step 2 registration

• Age >= 18 years

• Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achievehemoglobin [Hgb] >= 10.0 g/dl is acceptable) (within 7 days prior to step 2registration)

• Leukocytes >= 2,000/mm^3 (within 7 days prior to step 2 registration)

• Absolute neutrophil count >= 1,500/mm^3 (within 7 days prior to step 2 registration)

• Platelets >= 100,000/mm^3 (within 7 days prior to step 2 registration)

• Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) (within 7days prior to step 2 registration)

• Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5x ULN (within 7 days prior to step 2 registration)

• Alanine transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 xULN (within 7 days prior to step 2 registration)

• Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if usingthe Cockcroft-Gault formula) (within 7 days prior to step 2 registration)

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Patients witha history of hepatitis C virus (HCV) infection must have been treated and cured. Forpatients with HCV infection who are currently on treatment, they are eligible ifthey have an undetectable HCV viral load

• For women of childbearing potential (WOCBP), negative serum or urine pregnancy testwithin 7 days prior to step 2 registration. Note that it may need to be repeated ifnot also within 3 days prior to treatment start

• Women of childbearing potential (WOCBP) is defined as any female who hasexperienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.Menopause is defined clinically as 12 months of amenorrhea in a woman over 45in the absence of other biological or physiological causes

Exclusion Criteria:

• Prior therapy for tumor except for resection. For example, prior chemotherapy,immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viraltherapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection astreatment for the tumor, and/or any other antibody or drug specifically targetingT-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitialthermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, gamma knife,cyber knife, vaccine or other immunotherapy, brachytherapy, or convection enhanceddelivery;

• Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/duringsurgery to aid resection is not exclusionary and is not considered achemotherapy or intracerebral agent

• Current or planned treatment with any other investigational agents for the studycancer

• Definitive clinical or radiologic evidence of metastatic disease outside the brain

• Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer insitu and melanoma in situ) unless disease free for a minimum of 2 years

• Prior radiotherapy to the head or neck that would result in overlap of radiationtherapy fields

• Pregnancy and nursing females due to the potential teratogenic effects and potentialrisk for adverse events in nursing infants

• History of severe hypersensitivity reaction to any monoclonal antibody

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ipilimumab, nivolumab, or temozolomide

• On any dose of any systemically administered (oral, rectal, intravenous)corticosteroid within 3 days prior to step 2 registration. Inhaled, topical, andocular corticosteroids are allowed without limitation but must be recorded. Notethat treatment with systemically administered corticosteroid after initiating studytreatment is allowed as needed

• Patients with known immune impairment who may be unable to respond to anti-CTLA 4antibody

• History of interstitial lung disease including but not limited to sarcoidosis orpneumonitis

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, defined as New York HeartAssociation functional classification III/IV (Note: Patients with known history orcurrent symptoms of cardiac disease, or history of treatment with cardiotoxicagents, should have a clinical risk assessment of cardiac function using the NewYork Heart Association functional classification), unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS)

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, are excluded, as are patients on activeimmunosuppressive therapy. These include but are not limited to: patients with ahistory of immune-related neurologic disease, CNS or motor neuropathy, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis; systemic autoimmune disease such as autoimmune vasculitis [e.g.,Wegener's Granulomatosis]), systemic lupus erythematosus (SLE), connective tissuediseases (e.g., systemic progressive sclerosis), scleroderma, inflammatory boweldisease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a historyof toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipidsyndrome, Hashimoto's thyroiditis, autoimmune hepatitis are excluded because of therisk of recurrence or exacerbation of disease

• Exceptions: patients with a history of the following conditions are notexcluded, unless receiving active immunosuppressive therapy:

• Vitiligo

• Type I diabetes

• Rheumatoid arthritis and other arthropathies

• Sjogren's syndrome and psoriasis controlled with topical medication andpatients with positive serology, such as antinuclear antibodies (ANA)

• Anti-thyroid antibodies should be evaluated for the presence oftarget organ involvement and potential need for systemic treatmentbut should otherwise be eligible

• Patients who have evidence of active or acute diverticulitis, intra-abdominalabscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which areknown risk factors for bowel perforation are also excluded

• Current or planned therapy with warfarin