VXM01 Phase I Pilot Study in Patients With Operable Recurrence of a Glioblastoma

Study Overview
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Brief Summary
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VXM01 phase I pilot study in patients with operable recurrence of a glioblastoma to examine safety, tolerability, immune and biomarker response to the investigational VEGFR-2 DNA vaccine VXM01

Official Title
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VXM01 Phase I Pilot Study in Patients With Operable Recurrence of a Glioblastoma to Examine Safety, Tolerability, Immune and Biomarker Response to the Investigational VEGFR-2 DNA Vaccine VXM01

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: VXM01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent, signed and dated Histologically diagnosed intracranial supratentorial malignant glioma (contrast-enhancing anaplastic astrocytoma WHO Grade III or glioblastoma WHO Grade IV). Male or female patients who must be post-menopausal for at least 2 years or surgically sterile. Age ≥18 years Evidence of tumor progression following at least one therapy regimen that must have contained radiation and chemotherapy with temozolamid, as measured by MRI Candidates for a tumor reoperation Neurosurgical intervention should be postponable for 30 days Laboratory results (clinical chemistry, hematology, urine, liver enzymes, creatinine) without clinically relevant abnormalities Patients must be able to undergo MRI No concomitant medication with dexamethasone at the time of vaccination No active infection at the time of vaccination Karnofsky performance status >70 Appropriate hematologic parameters (for immunomonitoring): leukocytes ≥4.0 x 109 / L, lymphocytes ≥0.6 x 109 / L Tumor samples available for pathology review, central detection of T-cell responses in the peripheral blood and in the tumor tissue No medical or social conditions that may interfere with study outcome and follow-up Exclusion Criteria: Treatment in any other clinical trial within 30 days before screening Known positive test results for Hepatitis B surface antigen , hepatitis C virus antibodies, human immunodeficiency virus antibodies -1/-2 Any other condition or treatment that, in the opinion of the investigator, might interfere with the study or current drug or substance abuse Inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study Pregnancy or breast feeding Positive for anti-typhoid IgG/IgM antibodies according to the onsite test on Day 0 Cardiovascular disease defined as: Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg) Arterial thromboembolic event within 6 months before randomization including: Myocardial infarction Unstable angina pectoris Cerebrovascular accident Transient ischemic attack Congestive heart failure New York Heart Association grade III to IV Serious ventricular arrhythmia requiring medication Clinically significant peripheral artery disease > grade 2b according to Fontaine Intracranial ischemic stroke within 6 months before randomization History of intracranial hemorrhage Hemoptysis within 6 months before randomization Esophageal varices Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0) Significant traumatic injury or surgery within 4 weeks before randomization Non-healing wound, incomplete wound healing, bone fracture or any history of gastrointestinal ulcers within three years before inclusion, or positive gastroscopy within 3 months before inclusion Gastrointestinal fistula Thrombolysis therapy within 4 weeks before randomization Presence of any acute or chronic systemic infection Major surgical procedures, or open biopsy within 4 weeks before randomization Chronic concurrent therapy within 2 weeks before and during the treatment period up to Day 35 with: Corticosteroids (except steroids for adrenal failure or emesis prophylaxis up to 4 mg daily dose) or immunosuppressive agents Antibiotics Bevacizumab Any cancer anti-angiogenic treatment Chemotherapy from screening until reoperation (Day 35) Known multi-drug resistant gram-negative germ History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the study results or render the patient at high risk for treatment complications Women of childbearing potential Any condition which results in an undue risk for the patient during the study participation according to the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VXM01<br>VXM01 10E6 or 10E7 CFU | Drug: VXM01<br>* Oral immunotherapy targeting VEGFR2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability taking into account treatment-limiting toxicities (TLTs) | AEs listed together with information on onset, duration, severity, seriousness, relationship to the study drug, relationship to chemotherapy and to the underlying disease, outcome, and action taken. Frequency tables by System Organ Class and preferred term. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Response by Enzyme Linked Immuno Spot (ELISpot) | Patient-individual VEGFR-2 specific T cell responses will be determined by ELISpot using cryopreserved peripheral blood mononuclear cells | 12 months | 
| Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA) | Biomarkers including VEGF A and Collagen IV determined from periphaeral blood samples | 12 months | 
| Vascular normalization index (VNI) including tumor perfusion acc. to Sorensen 2009 | Determined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) (ktrans), dynamic susceptibility contrast imaging (DSC), blood volume maps (cerebral blood volume [CBV] of smaller vessels) and collagen IV | 12 months | 
| Tumor immune cell infiltration by tumor tissue immunohistochemistry | Tumor tissue immunohistochemistry staining including Evaluations of effector T cell infiltration, regulatory T-cells (Treg), myeloid derived suppressor cells (MDSC) | 35 days | 
| Tumor response or progression on MRI acc. to Response Assessment in Neuro-Oncology (RANO) criteria | MRI comprising the National Brain Tumor Society /EORTC protocol for gliomas | 12 months | 
| Clinical Response including time to progression, progression free survival, overall survival |  | 12 months | 
| Biodistribution and shedding of VXM01 bacteria | Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples | 10 days |