VXM01 Plus Avelumab Combination Study in Progressive Glioblastoma

NCT03750071

Last updated date
Study Location
CHU La Timone
Marseille, , 13005, France
Contact
+49 6221 567075

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Recurrent Glioblastoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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 (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

- 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 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 tumor samples available for pathology review, 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

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Cardiovascular disease defined as:


1. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood
pressure >100 mmHg)


2. Arterial thromboembolic event within 6 months before trial entry, including:


i. Myocardial infarction ii. Unstable angina pectoris iii. Cerebrovascular accident
iv. Transient ischemic attack


2. Congestive heart failure New York Heart Association grade III to IV


3. Serious ventricular arrhythmia requiring medication and arrhythmias requiring
Implantable Cardioverter Defibrillator (ICDs)


4. Clinically significant peripheral artery disease > grade 2b according to Fontaine


5. History of intracranial hemorrhage


6. Hemoptysis within 6 months before trial entry


7. Known oesophageal varices


8. Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0)


9. Significant traumatic injury or surgery within 4 weeks 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 months before
inclusion


11. Gastrointestinal fistula


12. Thrombolysis therapy within 4 weeks before trial entry


13. History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding that based on the investigator's 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 the tumor disease for this trial) within the
last 5 years (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:


1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
not requiring immunosuppressive treatment are eligible


2. Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable


17. History of uncontrolled intercurrent illness including but not limited to uncontrolled
diabetes (e.g., hemoglobin A1c ≥ 8%)


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 reactions to monoclonal antibodies (NCI CTCAE
v5.0 Grade ≥ 3)


19. 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 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 human immunodeficiency virus (HIV) or known acquired immunodeficiency
syndrome or multi-drug resistant gram-negative bacteria


23. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)


24. Women of childbearing potential


25. History of serious ophthalmological diseases, e.g. optic neuropathy, retinal
detachment, uveitis Prior and concomitant medication


26. Treatment in any other clinical trial within 30 days 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 weeks before and during the treatment period with:


1. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg daily
dose)


2. Immunosuppressive agents


3. Antibiotics


4. Bevacizumab or any other anti-angiogenic treatment


5. Any other anti-cancer therapy or concurrent anticancer treatment, for example,
cytoreductive therapy, radiotherapy [with the exception of palliative short
course, limited field (ie, ≤ 10 fractions and ≤ 30% bone marrow involvement or
per institutional standard) radiotherapy, which may be administered during the
study. However dosing must be suspended at least 14 days prior to the start of
radiotherapy and must not be resumed until at least 14 days after the last
radiotherapy fraction], immune therapy, or cytokine therapy, except for
erythropoietin


6. Administration of live vaccines (other than VXM01) within 30 days prior to study
treatment Other


29. Vaccination within 4 weeks 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; e.g., uncooperative attitude, inability to return for follow-up visits,
and improbability of completing the trial


32. Legal incapacity or limited legal capacity


33. Any condition which results in an undue risk for the patient during the trial
participation according to the investigator

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Recurrent GlioblastomaVXM01 Plus Avelumab Combination Study in Progressive Glioblastoma
NCT03750071
  1. Marseille,
  2. Utrecht,
  3. Heidelberg,
  4. Mannheim,
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE VXM01 Plus Avelumab Combination Study in Progressive Glioblastoma
Official Title  ICMJE 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
Brief Summary VXM01 in combination with avelumab in n=30 patients with progressive glioblastoma following standard treatment, with or without second surgery
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Recurrent Glioblastoma
Intervention  ICMJE
  • Biological: VXM01
    Ty21a transformed with a eukaryotic VEGFR-2 Expression Plasmid
    Other Name: Investigational VEGFR-2 DNA Vaccine
  • Biological: Avelumab
    Monoclonal anti-PD-L1 Antibody
    Other Name: Bavencio
Study Arms  ICMJE Experimental: VXM01/Avelumab
Combination of VXM01, Ty21a transformed with a eukaryotic expression cassette encoding VEGFR-2, and anti-PD-L1 Checkpoint Inhibitor Avelumab
Interventions:
  • Biological: VXM01
  • Biological: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 20, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 (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

    - 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 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 tumor samples available for pathology review, 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

Exclusion Criteria:

  1. Cardiovascular disease defined as:

    1. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg)
    2. Arterial thromboembolic event within 6 months before trial entry, including:

    i. Myocardial infarction ii. Unstable angina pectoris iii. Cerebrovascular accident iv. Transient ischemic attack

  2. Congestive heart failure New York Heart Association grade III to IV
  3. Serious ventricular arrhythmia requiring medication and arrhythmias requiring Implantable Cardioverter Defibrillator (ICDs)
  4. Clinically significant peripheral artery disease > grade 2b according to Fontaine
  5. History of intracranial hemorrhage
  6. Hemoptysis within 6 months before trial entry
  7. Known oesophageal varices
  8. Upper or lower gastrointestinal bleeding within 6 months before inclusion (Day 0)
  9. Significant traumatic injury or surgery within 4 weeks 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 months before inclusion
  11. Gastrointestinal fistula
  12. Thrombolysis therapy within 4 weeks before trial entry
  13. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that based on the investigator's 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 the tumor disease for this trial) within the last 5 years (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:

    1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
    2. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
  17. History of uncontrolled intercurrent illness including but not limited to uncontrolled diabetes (e.g., hemoglobin A1c ? 8%)
  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 reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ? 3)
  19. 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 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 human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome or multi-drug resistant gram-negative bacteria
  23. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
  24. Women of childbearing potential
  25. History of serious ophthalmological diseases, e.g. optic neuropathy, retinal detachment, uveitis Prior and concomitant medication
  26. Treatment in any other clinical trial within 30 days 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 weeks before and during the treatment period with:

    1. Corticosteroids (except steroids up to equivalent of dexamethasone 4 mg daily dose)
    2. Immunosuppressive agents
    3. Antibiotics
    4. Bevacizumab or any other anti-angiogenic treatment
    5. Any other anti-cancer therapy or concurrent anticancer treatment, for example, cytoreductive therapy, radiotherapy [with the exception of palliative short course, limited field (ie, ? 10 fractions and ? 30% bone marrow involvement or per institutional standard) radiotherapy, which may be administered during the study. However dosing must be suspended at least 14 days prior to the start of radiotherapy and must not be resumed until at least 14 days after the last radiotherapy fraction], immune therapy, or cytokine therapy, except for erythropoietin
    6. Administration of live vaccines (other than VXM01) within 30 days prior to study treatment Other
  29. Vaccination within 4 weeks 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; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial
  32. Legal incapacity or limited legal capacity
  33. Any condition which results in an undue risk for the patient during the trial participation according to the investigator
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Wolfgang Wick, MD+49 6221 567075[email protected]
Listed Location Countries  ICMJE France,   Germany,   Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03750071
Other Study ID Numbers  ICMJE VXM01-AVE-04-INT
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Vaximm GmbH
Study Sponsor  ICMJE Vaximm GmbH
Collaborators  ICMJE
  • Merck KGaA, Darmstadt, Germany
  • Pfizer
Investigators  ICMJE
Principal Investigator:Wolfgang Wick, MDUniversity Clinics Heidelberg
PRS Account Vaximm GmbH
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP