Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme

1. Signed informed consent.
2. Age ≥ 18 years.
3. Present with newly diagnosed supratentorial Glioblastoma (GBM) with a tissue diagnosis that has been established following either a surgical resection or biopsy. This includes treatment-naïve -(chemotherapy and radiotherapy)- patients with prior diagnosis of a lower grade astrocytoma that has been upgraded to a histologically verified GBM.
4. Karnofsky performance score of 70 or higher.
5. Patients entering the study must be on a stable dose of up to 12 mg (maximum) of Dexamethasone (or equivalent) daily for symptoms related to cerebral edema. Following the first dose of avelumab, the duration of treatment with the current dose of dexamethasone (maximum 12 mg/day) or equivalent, should be no more than 7 consecutive days. The investigator(s) should make every effort to taper the dexamethasone as soon as symptom improvement allows to the lowest tolerable dose that controls the CNS symptoms.
6. Will be or is undergoing or has received the standard therapy of chemo radiation therapy (60Gy in 30 fractions of 2Gy/day with concurrent temozolomide of 75mg/m2 per day PO) no more than 21 days ago.
7. Has not yet begun but will begin standard monthly temozolomide therapy.
8. Patient must have at least 1 formalin fixed paraffin embedded tumor tissue block representative of glioblastoma available for biomarker analysis and determination of MGMT status (if not already done). If tumor block is not available or not of adequate quality, sufficient pathology material, representative of glioblastoma, must be available.
9. Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused).
10. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN for all subjects.
11. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
12. Negative serum pregnancy test at screening for women of childbearing potential.
13. Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 60 days after avelumab treatment.

14. International normalized ratio (INR) or PT (secs) and activated partial thromboplastin time (aPTT):

    • in the absence of therapeutic intent to anticoagulate the subject: INR≤1.5 or PT ≤1.5 x ULN and aPTT ≤1.5 x ULN
    • in the presence of therapeutic intent to anticoagulate the subject: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution).

    NOTE: Use of full-dose anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to randomization.

15. Willing and able to comply with the protocol as judged by the Investigator

Exclusion Criteria:

1. Patients who have evidence of leptomeningeal disease.
2. Known significant pulmonary, cardiovascular, hepatic disorders or any other disease that in the opinion of the investigator would be contraindicated to receive anti PD-L1 therapy such as avelumab.
3. Prior treatment with bevacizumab or any checkpoint immune blockade thérapies.
4. Any other concomitant immunosuppressant other than temozolamide and steroids or any recent (within 3 months) experimental therapy.
5. Patients who have finished their radiotherapy course more than 3 weeks prior to Baseline.
6. Prior organ transplantation, including allogeneic stem cell transplantation.

7. Significant acute or chronic infections including, among others:

   • Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
   • Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive).

8. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:

   • Subjects with diabetes type I, vitiligo, psoriasis, hypo or hyperthyroid disease or any other autoimmune disease not requiring immunosuppressive treatment are at the investigator's discretion eligible
   • Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
   • Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
9. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
10. Pregnancy or lactation.
11. Known alcohol or drug abuse.
12. Any psychiatric or cognitive condition that would prohibit the understanding or rendering of informed consent.
13. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines.
14. Contraindication or intolerance to temozolomide.
15. Any other malignancy within 5 years prior to randomization, except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix.
16. Evidence of any active infection requiring hospitalization or IV antibiotics within 2 weeks prior to randomization.
17. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
18. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.