| Eligibility |
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.
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