Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma

Inclusion Criteria \[criteria apply to all cohorts unless otherwise specified\]: 1. Cohort A: Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for standard radiation therapy. 2. Cohorts B, B2, B3 and C: First or second recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) per modified Response Assessment in Neuro-oncology (RANO) criteria, with last baseline MRI confirmation within 14 days prior to Study Day 1. Note: Recurrence is defined as progression following therapy (i.e., chemotherapy; radiation). If the subject had a surgical resection for relapsed disease and no anti-tumor therapy was administered for up to 12 weeks, and the subject has further evidence of tumor growth or undergoes another resection, this will be considered as one episode of recurrence. 3. Cohorts B, B2, B3 and C: On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease outside of the radiation field or histopathologic confirmation of unequivocal tumor). 4. Cohorts B, B2, B3: No prior vascular endothelial growth factor (VEGF)/VEGF receptor targeted therapy; Cohort C: No more than one prior bevacizumab regimen. 5. Cohorts B, B2, B3 and C: Recovery from any prior treatment clinically significant, related adverse events to grade ≤ 1 or pretreatment baseline with the exception of alopecia and laboratory values listed per inclusion criteria. 6. Subjects with measurable or non-measurable disease. 7. Histopathologic confirmation of glioblastoma. 8. At the time of Study Day 1, subjects must be at least 4 weeks since major surgical procedure, open biopsy, or significant traumatic injury; there should be no anticipation of need for major surgical procedure during the course of the study. There should be no core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Study Day 1. 9. Subjects who have previously been treated with the Optune™ device are eligible for the study as long as toxicity related to the treatment has resolved to ≤ grade 1 or baseline. 10. Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky performance status of ≥ 70. 11. Adequate hematologic, renal and hepatic function, as defined below: * Absolute neutrophil count ≥ 1000/mm\^3; * Platelet count ≥ 100,000/mm\^3; * Total bilirubin ≤ 1.5 x upper limit of normal (ULN); or if subject has Gilbert syndrome, then total bilirubin ≤ 3 x ULN; * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN; * Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula): * Female CrCl = (140 - age in years) x weight in kg x 0.85/72 x serum creatinine in mg/dL; * Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL; * Cohorts B2, B3 and C: Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on dipstick, unless quantitative protein is \< 1000 mg in a 24-hour urine sample. 12. Age must be greater than or equal to 18 years at date of consent. 13. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] in the United States) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations. Exclusion Criteria \[criteria apply to all cohorts unless otherwise specified\]: 1. Primary tumors localized to the brain stem or spinal cord. 2. Locally directed therapies including but not limited to stereotactic radiosurgery, re-irradiation, Gliadel®, and therapeutics administered by direct injection or convection-enhanced delivery within 6 months of start of study treatment. 3. Prior exposure to durvalumab or other programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. 4. Presence of diffuse leptomeningeal disease or extracranial disease. 5. Active, suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and Hashimoto's thyroiditis). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 6. Known primary immunodeficiency or active human immunodeficiency virus. 7. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive test for hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid (hepatitis C virus antibody). 8. History of organ transplant requiring use of immunosuppressive medication. 9. History of active tuberculosis. 10. Significant active systemic illness including infections requiring intravenous antibiotics. 11. Current pneumonitis or interstitial lung disease. 12. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only. 13. History of severe allergic reactions to any unknown allergens or any components of the study drugs. 14. Any prior grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE. 15. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study. 16. Lack of availability for follow-up assessments. 17. Lack of availability for Post Study Follow-up contacts to determine relapse and survival. 18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin). 19. Women of childbearing potential not using a medically acceptable means of contraception for the duration of the study and unsterilized males not willing to abide by protocol-specified requirements for contraception. 20. If a subject previously received another investigational treatment, the last dose of investigational treatment was administered within 4 weeks of Day 1 of the study. 21. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk. 22. Cohorts B2, B3, and C: * Evidence of hemorrhage on the baseline MRI or computed tomography (CT) scan other than those that are ≤ grade 1 and either post-operative or stable on at least two consecutive scans; * Current use of warfarin sodium or any other Coumadin®-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to starting study drug. Low molecular weight heparin and Factor Xa antagonists are allowed; * History of clinically significant bleeding within 6 months of enrollment; * History of arterial thromboembolism within 12 months prior to enrollment; * Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 90 mmHg on antihypertensive medications); * Any prior history of hypertensive crisis or hypertensive encephalopathy; * Clinically significant cardiovascular disease within 12 months prior to enrollment (or randomization), including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent; * Evidence of bleeding diathesis or coagulopathy; * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment; * Serious, non-healing wound, ulcer, or bone fracture. 23. Subjects must not donate blood while on study and for at least 90 days following the last durvalumab treatment.