| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive glioblastoma (WHO grade IV) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To examine the safety and tolerability of VXM01 in combination with avelumab |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
• Efficacy of VXM01 in combination with avelumab by assessment of tumor objective response rate (ORR) per Immunotherapy Response
Assessment in Neuro-Oncology (iRANO) criteria and according to Okada et al., 2015 in non-resected and resected subjects (up to re-operation)
• Efficacy of VXM01 in combination with avelumab by assessment of clinical response
Exploratory objectives
• Effect of VXM01 plus avelumab on immuno- and biomarkers in tumor tissue and blood samples pre-and post-treatment
• To characterize the pharmacokinetics (PK) of avelumab in combination with VXM01
• To characterize the immunogenicity of avelumab in combination with VXM01
• To characterize the gut microbiome pre- and post treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (contrast-enhancing 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
Raditotherapy 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 (or most recently obtained available) tumor samples available for pathology review, panel sequencing, as well as 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 |
|
| E.4 | Principal exclusion criteria |
1. Cardiovascular disease:
- uncontrolled hypertension
- arterial thromboembolic event within 6 m before trial entry
2. Congestive heart failure NY Heart Association grade III to IV
3. Serious ventricular arrhythmia requiring medication and arrhythmias requiring ICD
4. Clinically significant peripheral artery disease > grade 2b according to Fontaine
5. History of relevant intracranial hemorrhage
6. Hemoptysis within 6 m before trial entry
7. Known oesophageal varices
8. Upper or lower gastrointestinal bleeding within 6 m before inclusion
9. Significant traumatic injury or surgery within 4 w 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 m before inclusion
11. Gastrointestinal fistula
12. Thrombolysis therapy within 4 w before trial entry
13. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that based on the investigators 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 glioblastoma) within the last 5 y (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:
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
b. Administration of steroids through a route known to result in a minimal systemic exposure are acceptable
17. History of uncontrolled intercurrent illness including but not limited to uncontrolled diabetes
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 to monoclonal antibodies (Grade ≥ 3)
19. Persisting toxicity related to prior therapy (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 HIV or known acquired immunodeficiency syndrome or multi-drug resistant gram-negative bacteria
23. HBV or HCV infection at screening
24. Women of childbearing potential
25. History of serious ophthalmological diseases, e.g. optic neuropathy, retinal detachment, uveitis
26. Treatment in any other clinical trial within 30 d 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 w before and during the treatment period with:
a. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg daily dose)
b. Immunosuppressive agents
c. Antibiotics (if required for any medical reason, antibiotics use should be avoided between 3 days before until 3 days after VXM01 administration)
d. Bevacizumab or any other anti-angiogenic treatment
e. Any other anti-cancer therapy or concurrent anticancer treatment
f. Administration of live vaccines (other than VXM01) within 30 days prior to study treatment
29. Vaccination within 4 w 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
32. Legal incapacity or limited legal capacity
33. Any condition which results in an undue risk for the patient during the trial participation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability up to 60 weeks after first IMP administration (incl. EoS visit, week 60) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every study visit up to and including EoS visit, week 60 |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints
• Best overall response (OR) and Duration of Response (DoR) on MRI according to iRANO in subjects with or without surgery prior to trial entry (up
to re-operation)
• Clinical response as assessed by time to progression (TTP), progression free survival (PFS), recurrence-free survival after re-operation (RFS) and
overall survival (OS) up to end of trial
Exploratory endpoints
• Patient-individual VEGFR-2 specific IFN-gamma T cell responses pre- and post-vaccination, determined by Enzyme Linked Immuno Spot (ELISpot) using cryopreserved peripheral blood mononuclear cells (all subjects)
• Frequency of peripheral regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) measured using flow cytometry analysis
• Tumor tissue immunohistochemistry / -fluorescence staining evaluations including, but not limited to, VEGFR-2 expression on tumor cells and tumor vasculature, effector T cell infiltration, Tregs, MDSCs, PD-1, PD-L1 (primary tumors of all subjects and recurrent tumors of re-operated subjects)
• Tumor PTEN mutation/deletion status (primary tumors of all subjects and recurrent tumors of re-operated subjects)
• Microsatellite instability (MSI) / DNA mismatch repair (MMR) status
• TCR sequencing of tumor infiltrating lymphocytes (TILs) and peripheral T cells.
• PK profile of avelumab in combination with VXM01
• Anti-avelumab anti-drug antibodies (ADA)
• Gut microbiome status |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration of VXM01 in combination with avelumab |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| When the last patient performs the EoS visit, under the standard protocol (i.e. without including any patient-specific prolongation treatment). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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