VXM01 Plus Avelumab Combination Study in Progressive Glioblastoma

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 yearsor surgically sterile
4. Age ≥18 years
5. Histologically diagnosed intracranial supratentorial malignant glioma (glioblastomaWHO Grade IV)
6. Evidence of tumor progression by RANO criteria following at least one prior therapyregimen that must have contained radiation and chemotherapy with temozolomide, asmeasured 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 havebeen transfused); INR <1.5x ULN. Subjects with documented benign cyclical neutropeniaare allowed if WBC count is ≥ 1.5 × 109/L with absolute neutrophil count ≥ 1.0 × 109/Land 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 limitof normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, and analanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with documentedmetastatic disease to the liver, AST and ALT levels ≤ 5 × ULN. Subjects withdocumented Gilbert disease are allowed if total bilirubin ≤ 3 x ULN
10. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/minaccording 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-cellresponses 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:
2. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic bloodpressure >100 mmHg)
3. Arterial thromboembolic event within 6 months before trial entry, including: i. Myocardial infarction ii. Unstable angina pectoris iii. Cerebrovascular accidentiv. Transient ischemic attack
4. Congestive heart failure New York Heart Association grade III to IV
5. Serious ventricular arrhythmia requiring medication and arrhythmias requiringImplantable Cardioverter Defibrillator (ICDs)
6. Clinically significant peripheral artery disease > grade 2b according to Fontaine
7. History of intracranial hemorrhage
8. Hemoptysis within 6 months before trial entry
9. Known oesophageal varices
10. Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0)
11. Significant traumatic injury or surgery within 4 weeks before trial entry
12. Non-healing wound, incomplete wound healing, bone fracture or gastrointestinal ulcerswithin three years before inclusion, or positive gastroscopy within 3 months beforeinclusion
13. Gastrointestinal fistula
14. Thrombolysis therapy within 4 weeks before trial entry
15. History of other disease, metabolic dysfunction, physical examination finding, orclinical laboratory finding that based on the investigator's judgement provides areasonable suspicion of a disease or condition that contraindicates the use of aninvestigational drug or that might affect the interpretation of the trial results orrender the patient at high risk for treatment complications
16. Previous malignant disease (other than the tumor disease for this trial) within thelast 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situof skin, bladder, cervix, colon/rectum, breast, or prostate) unless a completeremission without further recurrence was achieved at least 2 years prior to trialentry and the subject was deemed to have been cured with no additional therapyrequired or anticipated to be required
17. Prior organ transplantation, including allogeneic stem cell transplantation
18. Active autoimmune disease that might deteriorate when receiving an immunostimulatoryagent:
19. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid diseasenot requiring immunosuppressive treatment are eligible
20. Administration of steroids through a route known to result in a minimal systemicexposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
21. History of uncontrolled intercurrent illness including but not limited to uncontrolleddiabetes (e.g., hemoglobin A1c ≥ 8%)
22. Known prior hypersensitivity to investigational product or any component in itsformulations or any other drug scheduled or likely to be given during the trial,including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAEv5.0 Grade ≥ 3)
23. 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 asafety risk based on investigator's judgment are acceptable
24. Other severe acute or chronic medical conditions including immune colitis,inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior, or laboratory abnormalities that may increase the Risk associated with trialparticipation or trial treatment administration or may interfere with theinterpretation of trial results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this trial
25. Active infection requiring systemic therapy
26. Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiencysyndrome or multi-drug resistant gram-negative bacteria
27. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positiveHBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
28. Women of childbearing potential
29. History of serious ophthalmological diseases, e.g. optic neuropathy, retinaldetachment, uveitis Prior and concomitant medication
30. Treatment in any other clinical trial within 30 days or within 5 half lives of anyprior treatment, before screening
31. Any other condition or treatment that, in the opinion of the investigator, mightinterfere with the trial or current drug or substance abuse
32. Chronic concurrent therapy within 2 weeks before and during the treatment period with:
33. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg dailydose)
34. Immunosuppressive agents
35. Antibiotics
36. Bevacizumab or any other anti-angiogenic treatment
37. Any other anti-cancer therapy or concurrent anticancer treatment, for example,cytoreductive therapy, radiotherapy [with the exception of palliative shortcourse, limited field (ie, ≤ 10 fractions and ≤ 30% bone marrow involvement orper institutional standard) radiotherapy, which may be administered during thestudy. However dosing must be suspended at least 14 days prior to the start ofradiotherapy and must not be resumed until at least 14 days after the lastradiotherapy fraction], immune therapy, or cytokine therapy, except forerythropoietin
38. Administration of live vaccines (other than VXM01) within 30 days prior to studytreatment Other
39. Vaccination within 4 weeks of the first dose of avelumab and while on trials isprohibited except for administration of inactivated vaccines (other than VXM01)
40. Inability to understand the protocol requirements, instructions and trial-relatedrestrictions, the nature, scope, and possible consequences of the trial
41. Unlikely to comply with the protocol requirements, instructions and trial-relatedrestrictions; e.g., uncooperative attitude, inability to return for follow-up visits,and improbability of completing the trial
42. Legal incapacity or limited legal capacity
43. Any condition which results in an undue risk for the patient during the trialparticipation according to the investigator