Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

Inclusion Criteria: 1. Pathologically confirmed GBM (including all histologic variants); 2. Age ≥ 18 years; 3. Evidence of radiological (MRI-scan) measurable recurrent progressive GBM evaluated by the Response Assessment in Neuro-Oncology (RANO) criteria; 4. In arm B measurable disease according to the RANO guidelines, within 14 days of starting treatment. Measurable disease after surgery on arm A is not required with radiographic evidence of recurrent disease after treatment with temozolomide and radiotherapy; 5. An interval of at least 4 weeks between prior radiotherapy or chemotherapy and enrolment on this protocol; 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2; 7. Life expectancy, in the opinion of the investigator \> 3 month; 8. Written informed consent obtained prior to any screening procedures. Patients must be willing and able to comply with the protocol and aware of the investigational nature of this study; 9. Patients must have adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory criteria; 1. Hematopoietic function: total white blood cell count (WBC) ≥ 3000/mm³, absolute neutrophil count (ANC) ≥ 1500/mm³, platelet count ≥ 125,000/mm³; hemoglobin ≥ 9g/dL 2. Hepatic function: bilirubin \< 1.5 times the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be \< 4 times ULN), ALAT \< 2.5 times ULN; 3. Renal function: serum creatinine \< 1.5 ULN or estimated creatinine clearance of ≥ 50 mL/min, calculated using the formula of Cockcroft and Gault; 4. APTT and INR \< normal limit 10. All female patients and partners of childbearing potential must agree to use adequate birth control during study treatment and for 5 months after the last dose of study drug and have a negative serum pregnancy test at screening. Acceptable methods of contraception are oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, or a sexual partner who is surgically sterilized or post-menopausal. 11. Fertile males must be willing to employ adequate means of contraception during study treatment and for 7 months after the last dose of study drug; 12. Archived paraffin-embedded tissue (approximately 10 unstained slides or a tumor block) must be available for confirmation of tumor diagnosis and correlative studies; 13. Patients in the surgical arm (Arm A) must be predicted pre-operatively to have sufficiently sized recurrent tumor to allow for 500 mg of enhancing tumor and 300 mg of non-enhancing tumor to be resected; 14. Patients must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to MRI and maximum of a dose of 20 mg prednisolone per day at enrollment of the study. Exclusion Criteria: 1. Patients must not have significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; 2. Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids (equivalent to max dose of 20 mg prednisolone per day) and stable for at least 5 days prior to day 1; 3. Any condition (medical, social, psychological), which would prevent adequate information and follow-up; 4. Any other active malignancy or previous malignancies within the last 5 years, except, adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ; 5. Uncontrolled hypertension (systolic blood pressure (BP) \> 150 mmHg and/or diastolic BP \> 100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment; 6. Clinically significant peripheral vascular disease 7. Evidence of bleeding diathesis, coagulopathy or taking ASA, NSAIDs or clopidogrel; 8. Patients with coagulation problems and medically significant bleeding in the month prior to start of treatment (e.g., peptic ulcer, epistaxis, spontaneous bleeding); 9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the curse of the study; 10. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0; 11. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 0; 12. Known active hepatitis A, B or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); hepatitis testing is not required; 13. Known HIV infection; HIV testing is not required; 14. Active infection requiring parenteral systemic antibiotics; 15. Administration of a live, attenuated vaccine within 4 weeks before first dose of Nivolumab prior to surgery in Arm A or Cycle 1 Day 1 (Arm A and B) or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks before first dose of Nivolumab prior to surgery in Arm A or Cycle 1 Day 1 (Arm A and B) or at any time during the study; 16. Severe infections within 4 weeks prior to Cycle 1 Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia; 17. Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible; 18. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug; 19. Dementia or altered mental status that would prohibit informed consent; 20. History of organ allograft; 21. History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner´s granulomatosis, Sjogren´s syndrome, Bell´s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; 22. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted; 23. Pregnant or breast-feeding women 24. Prior treatment with PD-1/PD-L1 inhibitors 25. Known hypersensitivity to any of the components of Nivolumab or Bevacizumab; 26. Investigational therapy (defined as treatment for which there is no regulatory authority; within 28 days prior to Cycle 1 Day 1; 27. Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to Cycle 1 Day 1, with the following exceptions: a. Hormone-replacement therapy or oral contraceptives 28. Treatment with systemic immunosuppressive medications including, but not limited to: cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to Cycle 1, Day 1. The use of inhaled corticosteroids and mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed 29. Concurrent therapy with approved or investigational anticancer therapeutics; 30. Body weight significantly below ideal body weight in the opinion of the investigator.