Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma

Inclusion Criteria:

• STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration,patients known to have IDH mutation in the tumor on local or other testing areineligible and should not be registered)

• STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumortissue block and hematoxylin and eosin (H&E) stained slide to be sent for centralpathology review for confirmation of histology and MGMT promoter methylation status.Note that tissue for central pathology review and central MGMT assessment must bereceived by the New York University (NYU) Center for Biospecimen Research andDevelopment (CBRD) on or before postoperative calendar day 30. If tissue cannot bereceived by postoperative calendar day 30, then patients may NOT enroll on thistrial as central pathology review will not be complete in time for the patient tostart treatment no later than 8 weeks following surgery. Results of centralpathology review and central MGMT analysis will generally be completed within 10business days of receipt of tissue. Results will be entered by the central labdirectly into Rave. Note: In the event of an additional tumor resection(s), tissuemust be received within 30 days of the most recent resection and the latestresection must have been performed within 30 days after the initial resection.Surgical resection is required; stereotactic biopsy alone is not allowed because itwill not provide sufficient tissue for MGMT analysis

• STEP 1 REGISTRATION: Willing to use highly effective method of contraception forparticipants of childbearing potential (participants who may become pregnant or whomay impregnate a partner) during therapy and for 6 months after completingtreatment; this inclusion is necessary because the treatment in this study may besignificantly teratogenic

• STEP 1 REGISTRATION: The patient or a legally authorized representative must providestudy-specific informed consent prior to study entry and, for patients treated inthe United States (U.S.), authorization permitting release of personal healthinformation

• STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (orgliosarcoma as a subtype of glioblastoma) confirmed by central pathology review

• STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathologyreview. Note: Patients with tissue that is insufficient or inadequate for analysis,fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded

• Note: Any MGMT result other than methylated would require step 2 registrationto be reported as a "central review failure"

• STEP 2 REGISTRATION: Contrast-enhanced brain MRI performed either after surgery orprior to step 2 registration

• STEP 2 REGISTRATION: IDH mutation testing by at least one method (such asimmunohistochemistry for IDH1 R132H) must be performed as part of standard of careand no mutation must be found (i.e IDH wildtype). (If a mutation is identified thenthe patient will be ineligible and must be registered as ineligible at step 2.)

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

• STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days priorto step 2 registration

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

• STEP 2 REGISTRATION: Age 18-70 years

• STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or otherintervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable) (Within 14 daysprior to step 2 registration)

• STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3 (Within 14 days prior to step 2registration)

• STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3 (Within 14 days priorto step 2 registration)

• STEP 2 REGISTRATION: Platelets >= 100,000/mm^3 (Within 14 days prior to step 2registration)

• STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit ofnormal (ULN) (Within 14 days prior to step 2 registration)

• STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetictransaminase [SGOT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)

• STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvatetransaminase [SGPT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)

• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (Within 14 days prior to step 2registration)

• STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV)infection, the HBV viral load must be undetectable on suppressive therapy, ifindicated

• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg)indicating acute or chronic infection would make the patient ineligible unlessthe viral load becomes undetectable on suppressive therapy. Patients who areimmune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)

• STEP 2 REGISTRATION: For patients with a history of hepatitis C virus (HCV)infection must have been treated and cured. For patients with HCV infection who arecurrently on treatment, they are eligible if they have an undetectable HCV viralload

• Note: Known positive test for hepatitis C virus ribonucleic acid (HCVribonucleic acid [RNA]) indicating acute or chronic infection would make thepatient ineligible unless the viral load becomes undetectable on suppressivetherapy

• STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients oneffective anti-retroviral therapy with undetectable viral load within 6 months priorto step 2 registration are eligible for this trial. Testing is not required forentry into protocol

• STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons ofchildbearing potential) within 14 days prior to step 2 registration

• Childbearing potential is defined as any person who has experienced menarcheand who has not undergone surgical sterilization (hysterectomy or bilateraloophorectomy) or who is not postmenopausal

Exclusion Criteria:

• STEP 2 REGISTRATION: Prior therapy for tumor except for resection or prior laserinterstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy,or targeted therapy for GBM or lower grade glioma is disallowed (including but notlimited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab orother CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2antibody, vaccine therapy, polio or similar viral injection as treatment for thetumor, and/or any other antibody or drug specifically targeting T-cellco-stimulation or immune checkpoint pathways) as is Gliadel wafer, radiotherapy,radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanceddelivery

• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR)photodynamic therapy (PDT) or fluorescein administered prior to/during surgeryto aid resection is not exclusionary and is not considered a chemotherapy orintracerebral agent. Prior laser interstitial thermal therapy (LITT) is allowed

• STEP 2 REGISTRATION: Current or planned treatment with any other investigationalagents for the study cancer

• STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastaticdisease outside the brain

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

• STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result inoverlap of radiation therapy fields

• STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing dueto the potential teratogenic effects and potential risk for adverse events innursing infants

• STEP 2 REGISTRATION: History of allergic reactions attributed to compounds ofsimilar chemical or biologic composition to temozolomide or lomustine

• STEP 2 REGISTRATION: History of pulmonary fibrosis

• STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limitedto:

• Ongoing or active infection requiring intravenous (IV) antibiotics, IVantiviral, or IV antifungal treatment

• Symptomatic congestive heart failure, defined as New York Heart AssociationFunctional Classification III/IV (Note: Patients with known history or currentsymptoms of cardiac disease, or history of treatment with cardiotoxic agents,should have a clinical risk assessment of cardiac function using the New YorkHeart Association Functional Classification)

• Unstable angina pectoris within 6 months prior to Step 2 registration

• Uncontrolled cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• STEP 2 REGISTRATION: Evidence of diffuse leptomeningeal disease that requires wholebrain irradiation