<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03750071</url>
  </required_header>
  <id_info>
    <org_study_id>VXM01-AVE-04-INT</org_study_id>
    <nct_id>NCT03750071</nct_id>
  </id_info>
  <brief_title>VXM01 Plus Avelumab Combination Study in Progressive Glioblastoma</brief_title>
  <official_title>An Open-label, Phase I/II Multicenter Clinical Trial of VXM01 in Combination With Avelumab in Patients With Progressive Glioblastoma Following Standard Treatment, With or Without Second Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vaximm GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Vaximm GmbH</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      VXM01 in combination with avelumab in n=30 patients with progressive glioblastoma following&#xD;
      standard treatment, with or without second surgery&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The trial is conducted as a multicenter, open-label, Phase I/II trial to evaluate the&#xD;
      efficacy and safety of VXM01 in combination with avelumab in subjects with resectable and&#xD;
      non-resectable progressive glioblastoma following tumor resection and radiochemotherapy&#xD;
      containing temozolomide.&#xD;
&#xD;
      The trial will be performed in 30 subjects with progressive glioblastoma:&#xD;
&#xD;
        -  24 subjects who will not be candidates for a tumor re-operation (non-resectable&#xD;
           subjects)&#xD;
&#xD;
        -  6 subjects who will be candidates for a tumor re-operation (resectable subjects) The&#xD;
           trial, for each subject, will consist of a screening period, a treatment and&#xD;
           observatioon phase of 60 weeks including, a treatment phase of up to 48 weeks with prime&#xD;
           and boosting administrations of VXM01 in combination with avelumab and an observation&#xD;
           phase of 12 weeks and with an end of trial visit at Week 60.&#xD;
&#xD;
      Subjects will receive VXM01 in combination with avelumab up to Week 48. The end of study&#xD;
      (EoS) visit assessments will be performed Week 60.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 21, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Actual">December 31, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Treatment-emerging adverse events (safety and tolerability of VXM01 in combination with avelumab)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical response as assessed by time to progression (TTP)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>TTP is defined from the day of trial entry to the day of local tumor progression based on MRI (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical response as assessed by progression free survival (PFS)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>PFS is defined from the day of trial entry to the day of local tumor progression or recurrence after reoperation, based on MRI, or further positive biopsy, or the day of death of any cause. Subjects free of progression/recurrence will be censored at the day of last tumor assessment (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical response as assessed by recurrence-free survival after re-operation (RFS)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>RFS is defined from the day of trial entry to the day of recurrence after reoperation, based on MRI (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical response as assessed by Overall Survival (OS)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>OSOS will be defined by death of any cause and subjects alive at trial end will be censored at last contact day (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best overall response (OR) on MRI according to iRANO in subjects with or without surgery prior to trial entry (up to re-operation)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>The proportion of subjects with OR will be estimated together with 95% confidence intervals constructed using the binomial Distribution (in %)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) on MRI according to iRANO in subjects with or without surgery prior to trial entry (up to re-operation)</measure>
    <time_frame>Up to 60 weeks after first IMP administration</time_frame>
    <description>The DoR on MRI according to iRANO will be summarized descriptively for the two subgroups and illustrated using a Kaplan-Meier plot</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Recurrent Glioblastoma</condition>
  <arm_group>
    <arm_group_label>VXM01/Avelumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination of VXM01, Ty21a transformed with a eukaryotic expression cassette encoding VEGFR-2, and anti-PD-L1 Checkpoint Inhibitor Avelumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>VXM01</intervention_name>
    <description>Ty21a transformed with a eukaryotic VEGFR-2 Expression Plasmid</description>
    <arm_group_label>VXM01/Avelumab</arm_group_label>
    <other_name>Investigational VEGFR-2 DNA Vaccine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Monoclonal anti-PD-L1 Antibody</description>
    <arm_group_label>VXM01/Avelumab</arm_group_label>
    <other_name>Bavencio</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subjects who are able to understand and follow instructions during the trial&#xD;
&#xD;
          2. Ability and willingness to give written informed consent, signed and dated&#xD;
&#xD;
          3. Male or female subjects. Female subjects must be post-menopausal for at least 2 years&#xD;
             or surgically sterile&#xD;
&#xD;
          4. Age ≥18 years&#xD;
&#xD;
          5. Histologically diagnosed intracranial supratentorial malignant glioma (glioblastoma&#xD;
             WHO Grade IV)&#xD;
&#xD;
          6. Evidence of tumor progression by RANO criteria following at least one prior therapy&#xD;
             regimen that must have contained radiation and chemotherapy with temozolomide, as&#xD;
             measured by MRI&#xD;
&#xD;
             - Radiotherapy must have been completed at least 3 months prior to the inclusion visit&#xD;
&#xD;
          7. Candidates for a tumor reoperation (for the resectable arm [n=6] only)&#xD;
&#xD;
             - Neurosurgical intervention should be postponable for 30 days&#xD;
&#xD;
          8. Adequate bone marrow function including: Absolute neutrophil count (ANC) ≥1,500/mm3 or&#xD;
             ≥1.5 x 109/L; Platelets ≥ 100,000/mm3 or ≥100 x 109/L; Hemoglobin ≥ 9 g/dL (may have&#xD;
             been transfused); INR &lt;1.5x ULN. Subjects with documented benign cyclical neutropenia&#xD;
             are allowed if WBC count is ≥ 1.5 × 109/L with absolute neutrophil count ≥ 1.0 × 109/L&#xD;
             and appropriate hematology parameters: leukocytes ≥4.0 x 109 / L, lymphocytes ≥0.6 x&#xD;
             109/L&#xD;
&#xD;
          9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit&#xD;
             of normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, and an&#xD;
             alanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with documented&#xD;
             metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN. Subjects with&#xD;
             documented Gilbert disease are allowed if total bilirubin ≤ 3 x ULN&#xD;
&#xD;
         10. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min&#xD;
             according to the Cockcroft-Gault formula&#xD;
&#xD;
         11. Patients must be able to undergo MRI&#xD;
&#xD;
         12. Absence of active bacterial infection requiring antibiotic treatment&#xD;
&#xD;
         13. Karnofsky performance status ≥70&#xD;
&#xD;
         14. Primary tumor samples available for pathology review, central detection of T-cell&#xD;
             responses in the peripheral blood and in the tumor tissue&#xD;
&#xD;
         15. No medical or social conditions that may interfere with trial outcome and follow-up&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Cardiovascular disease defined as:&#xD;
&#xD;
               1. Uncontrolled hypertension (systolic blood pressure &gt;160 mmHg or diastolic blood&#xD;
                  pressure &gt;100 mmHg)&#xD;
&#xD;
               2. Arterial thromboembolic event within 6 months before trial entry, including:&#xD;
&#xD;
             i. Myocardial infarction ii. Unstable angina pectoris iii. Cerebrovascular accident&#xD;
             iv. Transient ischemic attack&#xD;
&#xD;
          2. Congestive heart failure New York Heart Association grade III to IV&#xD;
&#xD;
          3. Serious ventricular arrhythmia requiring medication and arrhythmias requiring&#xD;
             Implantable Cardioverter Defibrillator (ICDs)&#xD;
&#xD;
          4. Clinically significant peripheral artery disease &gt; grade 2b according to Fontaine&#xD;
&#xD;
          5. History of intracranial hemorrhage&#xD;
&#xD;
          6. Hemoptysis within 6 months before trial entry&#xD;
&#xD;
          7. Known oesophageal varices&#xD;
&#xD;
          8. Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0)&#xD;
&#xD;
          9. Significant traumatic injury or surgery within 4 weeks before trial entry&#xD;
&#xD;
         10. Non-healing wound, incomplete wound healing, bone fracture or gastrointestinal ulcers&#xD;
             within three years before inclusion, or positive gastroscopy within 3 months before&#xD;
             inclusion&#xD;
&#xD;
         11. Gastrointestinal fistula&#xD;
&#xD;
         12. Thrombolysis therapy within 4 weeks before trial entry&#xD;
&#xD;
         13. History of other disease, metabolic dysfunction, physical examination finding, or&#xD;
             clinical laboratory finding that based on the investigator's judgement provides a&#xD;
             reasonable suspicion of a disease or condition that contraindicates the use of an&#xD;
             investigational drug or that might affect the interpretation of the trial results or&#xD;
             render the patient at high risk for treatment complications&#xD;
&#xD;
         14. Previous malignant disease (other than the tumor disease for this trial) within the&#xD;
             last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ&#xD;
             of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete&#xD;
             remission without further recurrence was achieved at least 2 years prior to trial&#xD;
             entry and the subject was deemed to have been cured with no additional therapy&#xD;
             required or anticipated to be required&#xD;
&#xD;
         15. Prior organ transplantation, including allogeneic stem cell transplantation&#xD;
&#xD;
         16. Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent:&#xD;
&#xD;
               1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease&#xD;
                  not requiring immunosuppressive treatment are eligible&#xD;
&#xD;
               2. Administration of steroids through a route known to result in a minimal systemic&#xD;
                  exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable&#xD;
&#xD;
         17. History of uncontrolled intercurrent illness including but not limited to uncontrolled&#xD;
             diabetes (e.g., hemoglobin A1c ≥ 8%)&#xD;
&#xD;
         18. Known prior hypersensitivity to investigational product or any component in its&#xD;
             formulations or any other drug scheduled or likely to be given during the trial,&#xD;
             including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE&#xD;
             v5.0 Grade ≥ 3)&#xD;
&#xD;
         19. Persisting toxicity related to prior therapy (NCI CTCAE v5.0 Grade &gt; 1); however,&#xD;
             alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 AEs not constituting a&#xD;
             safety risk based on investigator's judgment are acceptable&#xD;
&#xD;
         20. Other severe acute or chronic medical conditions including immune colitis,&#xD;
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric&#xD;
             conditions including recent (within the past year) or active suicidal ideation or&#xD;
             behavior, or laboratory abnormalities that may increase the Risk associated with trial&#xD;
             participation or trial treatment administration or may interfere with the&#xD;
             interpretation of trial results and, in the judgment of the investigator, would make&#xD;
             the patient inappropriate for entry into this trial&#xD;
&#xD;
         21. Active infection requiring systemic therapy&#xD;
&#xD;
         22. Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency&#xD;
             syndrome or multi-drug resistant gram-negative bacteria&#xD;
&#xD;
         23. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive&#xD;
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)&#xD;
&#xD;
         24. Women of childbearing potential&#xD;
&#xD;
         25. History of serious ophthalmological diseases, e.g. optic neuropathy, retinal&#xD;
             detachment, uveitis Prior and concomitant medication&#xD;
&#xD;
         26. Treatment in any other clinical trial within 30 days or within 5 half lives of any&#xD;
             prior treatment, before screening&#xD;
&#xD;
         27. Any other condition or treatment that, in the opinion of the investigator, might&#xD;
             interfere with the trial or current drug or substance abuse&#xD;
&#xD;
         28. Chronic concurrent therapy within 2 weeks before and during the treatment period with:&#xD;
&#xD;
               1. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg daily&#xD;
                  dose)&#xD;
&#xD;
               2. Immunosuppressive agents&#xD;
&#xD;
               3. Antibiotics&#xD;
&#xD;
               4. Bevacizumab or any other anti-angiogenic treatment&#xD;
&#xD;
               5. Any other anti-cancer therapy or concurrent anticancer treatment, for example,&#xD;
                  cytoreductive therapy, radiotherapy [with the exception of palliative short&#xD;
                  course, limited field (ie, ≤ 10 fractions and ≤ 30% bone marrow involvement or&#xD;
                  per institutional standard) radiotherapy, which may be administered during the&#xD;
                  study. However dosing must be suspended at least 14 days prior to the start of&#xD;
                  radiotherapy and must not be resumed until at least 14 days after the last&#xD;
                  radiotherapy fraction], immune therapy, or cytokine therapy, except for&#xD;
                  erythropoietin&#xD;
&#xD;
               6. Administration of live vaccines (other than VXM01) within 30 days prior to study&#xD;
                  treatment Other&#xD;
&#xD;
         29. Vaccination within 4 weeks of the first dose of avelumab and while on trials is&#xD;
             prohibited except for administration of inactivated vaccines (other than VXM01)&#xD;
&#xD;
         30. Inability to understand the protocol requirements, instructions and trial-related&#xD;
             restrictions, the nature, scope, and possible consequences of the trial&#xD;
&#xD;
         31. Unlikely to comply with the protocol requirements, instructions and trial-related&#xD;
             restrictions; e.g., uncooperative attitude, inability to return for follow-up visits,&#xD;
             and improbability of completing the trial&#xD;
&#xD;
         32. Legal incapacity or limited legal capacity&#xD;
&#xD;
         33. Any condition which results in an undue risk for the patient during the trial&#xD;
             participation according to the investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wolfgang Wick, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Clinics Heidelberg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Neurology Clinic and National Center for Tumor Diseases</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Clinic</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <removed_countries>
    <country>France</country>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>October 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>October 19, 2022</last_update_submitted>
  <last_update_submitted_qc>October 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Avelumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03750071
org study id: VXM01-AVE-04-INT
nct id: NCT03750071
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
VXM01 in combination with avelumab in n=30 patients with progressive glioblastoma following
      standard treatment, with or without second surgery
The trial is conducted as a multicenter, open-label, Phase I/II trial to evaluate the
      efficacy and safety of VXM01 in combination with avelumab in subjects with resectable and
      non-resectable progressive glioblastoma following tumor resection and radiochemotherapy
      containing temozolomide.

      The trial will be performed in 30 subjects with progressive glioblastoma:

        -  24 subjects who will not be candidates for a tumor re-operation (non-resectable
           subjects)

        -  6 subjects who will be candidates for a tumor re-operation (resectable subjects) The
           trial, for each subject, will consist of a screening period, a treatment and
           observatioon phase of 60 weeks including, a treatment phase of up to 48 weeks with prime
           and boosting administrations of VXM01 in combination with avelumab and an observation
           phase of 12 weeks and with an end of trial visit at Week 60.

      Subjects will receive VXM01 in combination with avelumab up to Week 48. The end of study
      (EoS) visit assessments will be performed Week 60.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Treatment-emerging adverse events (safety and tolerability of VXM01 in combination with avelumab)
time frame: Up to 60 weeks after first IMP administration
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.
measure: Clinical response as assessed by time to progression (TTP)
time frame: Up to 60 weeks after first IMP administration
description: TTP is defined from the day of trial entry to the day of local tumor progression based on MRI (in days)
measure: Clinical response as assessed by progression free survival (PFS)
time frame: Up to 60 weeks after first IMP administration
description: PFS is defined from the day of trial entry to the day of local tumor progression or recurrence after reoperation, based on MRI, or further positive biopsy, or the day of death of any cause. Subjects free of progression/recurrence will be censored at the day of last tumor assessment (in days)
measure: Clinical response as assessed by recurrence-free survival after re-operation (RFS)
time frame: Up to 60 weeks after first IMP administration
description: RFS is defined from the day of trial entry to the day of recurrence after reoperation, based on MRI (in days)
measure: Clinical response as assessed by Overall Survival (OS)
time frame: Up to 60 weeks after first IMP administration
description: OSOS will be defined by death of any cause and subjects alive at trial end will be censored at last contact day (in days)
measure: Best overall response (OR) on MRI according to iRANO in subjects with or without surgery prior to trial entry (up to re-operation)
time frame: Up to 60 weeks after first IMP administration
description: The proportion of subjects with OR will be estimated together with 95% confidence intervals constructed using the binomial Distribution (in %)
measure: Duration of Response (DoR) on MRI according to iRANO in subjects with or without surgery prior to trial entry (up to re-operation)
time frame: Up to 60 weeks after first IMP administration
description: The DoR on MRI according to iRANO will be summarized descriptively for the two subgroups and illustrated using a Kaplan-Meier plot
arm group label: VXM01/Avelumab
arm group type: Experimental
description: Combination of VXM01, Ty21a transformed with a eukaryotic expression cassette encoding VEGFR-2, and anti-PD-L1 Checkpoint Inhibitor Avelumab
intervention type: Biological
intervention name: VXM01
description: Ty21a transformed with a eukaryotic VEGFR-2 Expression Plasmid
arm group label: VXM01/Avelumab
other name: Investigational VEGFR-2 DNA Vaccine
intervention type: Biological
intervention name: Avelumab
description: Monoclonal anti-PD-L1 Antibody
arm group label: VXM01/Avelumab
other name: Bavencio
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wolfgang Wick, MD
role: Principal Investigator
affiliation: University Clinics Heidelberg
facility: 
facility: 
country: Germany
country: France
country: Netherlands
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Avelumab
sharing ipd: No