VXM01 Phase I Pilot Study in Patients With Operable Recurrence of a Glioblastoma
Primary Purpose
Glioblastoma
Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
VXM01
Sponsored by
About this trial
This is an interventional treatment trial for Glioblastoma
Eligibility Criteria
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
Sites / Locations
- Neurology Clinic and National Center for Tumor Diseases
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
VXM01
Arm Description
VXM01 10E6 or 10E7 CFU
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA)
Biomarkers including VEGF A and Collagen IV determined from periphaeral blood samples
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
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)
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
Clinical Response including time to progression, progression free survival, overall survival
Biodistribution and shedding of VXM01 bacteria
Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02718443
Brief Title
VXM01 Phase I Pilot Study in Patients With Operable Recurrence of a Glioblastoma
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
May 2016 (undefined)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
July 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vaximm GmbH
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
VXM01
Arm Type
Experimental
Arm Description
VXM01 10E6 or 10E7 CFU
Intervention Type
Drug
Intervention Name(s)
VXM01
Intervention Description
Oral immunotherapy targeting VEGFR2
Primary Outcome Measure Information:
Title
Safety and tolerability taking into account treatment-limiting toxicities (TLTs)
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Immune Response by Enzyme Linked Immuno Spot (ELISpot)
Description
Patient-individual VEGFR-2 specific T cell responses will be determined by ELISpot using cryopreserved peripheral blood mononuclear cells
Time Frame
12 months
Title
Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA)
Description
Biomarkers including VEGF A and Collagen IV determined from periphaeral blood samples
Time Frame
12 months
Title
Vascular normalization index (VNI) including tumor perfusion acc. to Sorensen 2009
Description
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
Time Frame
12 months
Title
Tumor immune cell infiltration by tumor tissue immunohistochemistry
Description
Tumor tissue immunohistochemistry staining including Evaluations of effector T cell infiltration, regulatory T-cells (Treg), myeloid derived suppressor cells (MDSC)
Time Frame
35 days
Title
Tumor response or progression on MRI acc. to Response Assessment in Neuro-Oncology (RANO) criteria
Description
MRI comprising the National Brain Tumor Society /EORTC protocol for gliomas
Time Frame
12 months
Title
Clinical Response including time to progression, progression free survival, overall survival
Time Frame
12 months
Title
Biodistribution and shedding of VXM01 bacteria
Description
Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples
Time Frame
10 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wolfgang Wick, MD
Organizational Affiliation
Neurology Clinic and National Center for Tumor Diseases
Official's Role
Principal Investigator
Facility Information:
Facility Name
Neurology Clinic and National Center for Tumor Diseases
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
Learn more about this trial
VXM01 Phase I Pilot Study in Patients With Operable Recurrence of a Glioblastoma
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