| Eligibility |
Inclusion Criteria:
1. Subjects who are able to understand and follow instructions during the trial
2. Ability and willingness to give written informed consent, signed and dated
3. Male or female subjects. Female subjects must be post-menopausal for at least 2 years
or surgically sterile
4. Age =18 years
5. Histologically diagnosed intracranial supratentorial malignant glioma (glioblastoma
WHO Grade IV)
6. Evidence of tumor progression by RANO criteria following at least one prior therapy
regimen that must have contained radiation and chemotherapy with temozolomide, as
measured by MRI
- Radiotherapy must have been completed at least 3 months prior to the inclusion visit
7. Candidates for a tumor reoperation (for the resectable arm [n=6] only)
- Neurosurgical intervention should be postponable for 30 days
8. Adequate bone marrow function including: Absolute neutrophil count (ANC) =1,500/mm3 or
=1.5 x 109/L; Platelets = 100,000/mm3 or =100 x 109/L; Hemoglobin = 9 g/dL (may have
been transfused); INR <1.5x ULN. Subjects with documented benign cyclical neutropenia
are allowed if WBC count is = 1.5 × 109/L with absolute neutrophil count = 1.0 × 109/L
and appropriate hematology parameters: leukocytes =4.0 x 109 / L, lymphocytes =0.6 x
109/L
9. Adequate hepatic function defined by a total bilirubin level = 1.5 × the upper limit
of normal range (ULN), an aspartate aminotransferase (AST), level = 2.5 × ULN, and an
alanine aminotransferase (ALT) level = 2.5 × ULN or, for subjects with documented
metastatic disease to the liver, AST and ALT levels = 5 × ULN. Subjects with
documented Gilbert disease are allowed if total bilirubin = 3 x ULN
10. Adequate renal function defined by an estimated creatinine clearance = 30 mL/min
according to the Cockcroft-Gault formula
11. Patients must be able to undergo MRI
12. Absence of active bacterial infection requiring antibiotic treatment
13. Karnofsky performance status =70
14. Primary tumor samples available for pathology review, central detection of T-cell
responses in the peripheral blood and in the tumor tissue
15. No medical or social conditions that may interfere with trial outcome and follow-up
Exclusion Criteria:
1. Cardiovascular disease defined as:
1. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood
pressure >100 mmHg)
2. Arterial thromboembolic event within 6 months before trial entry, including:
i. Myocardial infarction ii. Unstable angina pectoris iii. Cerebrovascular accident
iv. Transient ischemic attack
2. Congestive heart failure New York Heart Association grade III to IV
3. Serious ventricular arrhythmia requiring medication and arrhythmias requiring
Implantable Cardioverter Defibrillator (ICDs)
4. Clinically significant peripheral artery disease > grade 2b according to Fontaine
5. History of intracranial hemorrhage
6. Hemoptysis within 6 months before trial entry
7. Known oesophageal varices
8. Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0)
9. Significant traumatic injury or surgery within 4 weeks before trial entry
10. Non-healing wound, incomplete wound healing, bone fracture or gastrointestinal ulcers
within three years before inclusion, or positive gastroscopy within 3 months before
inclusion
11. Gastrointestinal fistula
12. Thrombolysis therapy within 4 weeks before trial entry
13. History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding that based on the investigator's judgement provides a
reasonable suspicion of a disease or condition that contraindicates the use of an
investigational drug or that might affect the interpretation of the trial results or
render the patient at high risk for treatment complications
14. Previous malignant disease (other than the tumor disease for this trial) within the
last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ
of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete
remission without further recurrence was achieved at least 2 years prior to trial
entry and the subject was deemed to have been cured with no additional therapy
required or anticipated to be required
15. Prior organ transplantation, including allogeneic stem cell transplantation
16. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent:
1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
not requiring immunosuppressive treatment are eligible
2. Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
17. History of uncontrolled intercurrent illness including but not limited to uncontrolled
diabetes (e.g., hemoglobin A1c = 8%)
18. Known prior hypersensitivity to investigational product or any component in its
formulations or any other drug scheduled or likely to be given during the trial,
including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE
v5.0 Grade = 3)
19. Persisting toxicity related to prior therapy (NCI CTCAE v5.0 Grade > 1); however,
alopecia, sensory neuropathy Grade = 2, or other Grade = 2 AEs not constituting a
safety risk based on investigator's judgment are acceptable
20. Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune 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 trial
participation or trial treatment administration or may interfere with the
interpretation of trial results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this trial
21. Active infection requiring systemic therapy
22. Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency
syndrome or multi-drug resistant gram-negative bacteria
23. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
24. Women of childbearing potential
25. History of serious ophthalmological diseases, e.g. optic neuropathy, retinal
detachment, uveitis Prior and concomitant medication
26. Treatment in any other clinical trial within 30 days or within 5 half lives of any
prior treatment, before screening
27. Any other condition or treatment that, in the opinion of the investigator, might
interfere with the trial or current drug or substance abuse
28. Chronic concurrent therapy within 2 weeks before and during the treatment period with:
1. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg daily
dose)
2. Immunosuppressive agents
3. Antibiotics
4. Bevacizumab or any other anti-angiogenic treatment
5. Any other anti-cancer therapy or concurrent anticancer treatment, for example,
cytoreductive therapy, radiotherapy [with the exception of palliative short
course, limited field (ie, = 10 fractions and = 30% bone marrow involvement or
per institutional standard) radiotherapy, which may be administered during the
study. However dosing must be suspended at least 14 days prior to the start of
radiotherapy and must not be resumed until at least 14 days after the last
radiotherapy fraction], immune therapy, or cytokine therapy, except for
erythropoietin
6. Administration of live vaccines (other than VXM01) within 30 days prior to study
treatment Other
29. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines (other than VXM01)
30. Inability to understand the protocol requirements, instructions and trial-related
restrictions, the nature, scope, and possible consequences of the trial
31. Unlikely to comply with the protocol requirements, instructions and trial-related
restrictions; e.g., uncooperative attitude, inability to return for follow-up visits,
and improbability of completing the trial
32. Legal incapacity or limited legal capacity
33. Any condition which results in an undue risk for the patient during the trial
participation according to the investigator
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