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Study to Evaluate Safety, Tolerability, and Optimal Dose of Candidate GBM Vaccine VBI-1901 in Recurrent GBM Subjects

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ClinicalTrials.gov Identifier: NCT03382977
Recruitment Status : Active, not recruiting
First Posted : December 26, 2017
Last Update Posted : November 5, 2020
Sponsor:
Information provided by (Responsible Party):
VBI Vaccines Inc.

Tracking Information
First Submitted Date  ICMJE November 23, 2017
First Posted Date  ICMJE December 26, 2017
Last Update Posted Date November 5, 2020
Actual Study Start Date  ICMJE December 6, 2017
Actual Primary Completion Date October 14, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 29, 2019)
Dose limiting toxicity (DLT) occurring during Part A of the study and the occurrence of AEs during each treatment cycle in both Part A and Part B of the study [ Time Frame: For DLT in Part A, analysis will be based on the occurrence of Adverse Events (AEs) from first injection at Day 1 to Day 14. Analysis of AEs in Part A and Part B will be based on the occurrence of AEs until 28 days post injection ]
Dose limiting toxicity (DLT) occurring during Part A and the occurrence of AEs in Part A and B of the study
Original Primary Outcome Measures  ICMJE
 (submitted: December 18, 2017)
Dose limiting toxicity (DLT) occurring during part A of the study [ Time Frame: Analysis will be based on the occurrence of Adverse Events (AEs) from first injection at Day 1 to Day 14 ]
Dose limiting toxicity (DLT) occurring during part A of the study
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2019)
  • Immunogenicity and optimal vaccine-induced immunity-serum IgG anti-gB antibodies (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine until tumor progression or toxicity ]
    Serum IgG anti-gB antibody titers in baseline and post vaccination samples.
  • Cellular immunity against HCMV gB and pp65 antigens (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine ]
    Cellular immunity against HCMV gB and pp65 antigens using IFN-γ and IL-5 ELISPOT assessed at baseline and 2 weeks after each vaccination. Results will be provided as frequencies of IFN-γ and IL-5 spots/3x105 peripheral blood mononuclear cells (PBMCs) post HCMV stimulation at baseline and after each vaccination.
  • Changes in frequencies of myeloid suppressor cells and regulatory T cells (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine ]
    Additional exploratory immunological measurements, including changes in the frequency of myeloid suppressor cells and regulatory T cells (Tregs)
  • Progression free survival (PFS) (Part A and B) [ Time Frame: From the date of first dose to date of progression or death, as well as at 6 months and 12 months ]
    Progression free survival (PFS) from date of first dose to date of progression (according to iRANO criteria) or death, as well as at 6 months and 12 months. Subject who stop treatment for causes other than progression may be censored if other therapy is initiated or if regular assessments for assessing progression are no longer available.
  • Overall survival (OS) (Part A and B) [ Time Frame: 6 months and 12 months from date of first dose ]
    Overall survival (OS) at 6 months and 12 months from date of first dose
  • Median overall survival (Part A and B) [ Time Frame: Date of first dose to date of death from any cause, assessed up to 18 months ]
    Median overall survival
  • Reduction in steroid use compared to baseline (Part A and B) [ Time Frame: Baseline to study completion, an average of 12 months ]
    Reduction in steroid use compared to baseline
  • Change in quality of life (QOL questionnaire) compared to baseline (Part A and B) [ Time Frame: Baseline to study completion, an average of 12 months ]
    Change in quality of life (QOL questionnaire) compared to baseline
  • Immunogenicity of the optimal dose of VBI-1901 formulated with either GM-CSF or AS01B adjuvants (Part B). [ Time Frame: Baseline and 2 weeks after each dose of vaccine until tumor progression or toxicity ]
    Part B of the Study will evaluate the safety, immunogenicity and patient survival at an optimal dose of VBI-1901 as outlined in Part A. A correlation with clinical outcomes listed above in addition to tumor response will also be determined.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2017)
  • Immunogenicity and optimal vaccine-induced immunity-serum IgG anti-gB antibodies (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine until tumor progression or toxicity ]
    Serum IgG anti-gB antibody titers in baseline and post vaccination samples.
  • Cellular immunity against HCMV gB and pp65 antigens (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine ]
    Cellular immunity against HCMV gB and pp65 antigens using IFN-γ and IL-5 ELISPOT assessed at baseline and 2 weeks after each vaccination. Results will be provided as frequencies of IFN-γ and IL-5 spots/3x105 PBMCs post HCMV stimulation at baseline and after each vaccination.
  • Changes in frequencies of myeloid suppressor cells and regulatory T cells (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine ]
    Additional exploratory immunological measurements, including changes in the frequency of myeloid suppressor cells and regulatory T cells (Tregs).
  • Progression free survival (PFS) (Part A and B) [ Time Frame: Date of first dose to date of progression and 6 and 12 months ]
    Progression free survival (PFS) from date of first dose to date of progression (according to iRANO criteria) or death, as well as at 6 months and 12 months. Subject who stop treatment for causes other than progression may be censored if other therapy is initiated or if regular assessments for assessing progression are no longer available.
  • Overall survival (OS) (Part A and B) [ Time Frame: 6 months and 12 months from date of first dose ]
    Overall survival (OS) at 6 months and 12 months from date of first dose.
  • Median overall survival (Part A and B) [ Time Frame: Date of first dose to date of death from any cause, assessed up to 18 months ]
    Median overall survival
  • Reduction in steroid use compared to baseline.(Part A and B) [ Time Frame: Baseline to study completion, an average of 12 months ]
    Reduction in steroid use compared to baseline
  • Change in quality of life (QOL questionnaire) compared to baseline (Part A and B) [ Time Frame: Baseline to study completion, an average of 12 months ]
    Change in quality of life (QOL questionnaire) compared to baseline
  • Immunogenicity and optimal vaccine-induced immunity-fold-induction (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine until tumor progression or toxicity ]
    ratio of baseline/ post vaccination antibody titers (fold-induction).
  • Immunogenicity and optimal vaccine-induced immunity-2-fold (or higher) increase (Part A and B) [ Time Frame: Baseline and 2 weeks after each dose of vaccine until tumor progression or toxicity ]
    % of subjects achieving a 2-fold (or higher) increase of anti-HCMV gB antibodies compared to baseline.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate Safety, Tolerability, and Optimal Dose of Candidate GBM Vaccine VBI-1901 in Recurrent GBM Subjects
Official Title  ICMJE A Two-part, Phase I/IIA Dose-Escalation Study to Define the Safety, Tolerability, and Optimal Dose of Candidate GBM Vaccine VBI-1901 With Subsequent Extension of Optimal Dose in Recurrent GBM Subjects
Brief Summary The purpose of this study is to assess the safety and tolerability of VBI-1901 in subjects with Recurrent GBM.
Detailed Description This is a two-part, dose-escalation study to define the safety, tolerability, and optimal dose level of candidate GBM vaccine VBI-1901 with subsequent extension of optimal dose level in recurrent GBM subjects. Subjects in the dose escalation (Part A of trial) as well as extension phase of the trial (Part B) will continue to receive vaccine every 4 weeks until tumor progression per iRANO criteria.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

3+ 3 Dose Escalation

Therapeutic Vaccine: VBI-1901

The vaccine is formulated with GM-CSF and administered intradermally (ID) or AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Masking: None (Open Label)
Masking Description:
None, open-label Allocation (FDAAA)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE Biological: VBI-1901
The vaccine is formulated with GM-CSF and administered intradermally (ID) or AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.
Study Arms  ICMJE
  • Experimental: Dose Level 1
    VBI-1901 low dose (0.4 μg pp65 content) vaccine formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal intradermal injections
    Intervention: Biological: VBI-1901
  • Experimental: Dose Level 2
    VBI-1901 intermediate dose (2 μg pp65 content) vaccine formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal intradermal injections
    Intervention: Biological: VBI-1901
  • Experimental: Dose Level 3
    VBI-1901 high dose (10 μg pp65 content) vaccine formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal intradermal injections
    Intervention: Biological: VBI-1901
  • Experimental: Dose Level 4
    VBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal ID injections.
    Intervention: Biological: VBI-1901
  • Experimental: Dose Level 5
    VBI-1901 10 μg HCMV pp65 formulated with AS01B (50 μg of QS-21 and 50 μg of MPL per dose) in 1.0 mL volume, given in one IM injection
    Intervention: Biological: VBI-1901
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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 29, 2019)
38
Original Estimated Enrollment  ICMJE
 (submitted: December 18, 2017)
18
Estimated Study Completion Date  ICMJE November 2020
Actual Primary Completion Date October 14, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

PART A DOSE ESCALATION

Inclusion Criteria: Part A Dose Escalation

  1. 18-70 years of age
  2. Histologically confirmed WHO grade IV glioblastoma
  3. Unequivocal evidence of a tumor recurrence (any number of recurrences) or progression after an initial treatment regimen (prior to enrollment on this study) as assessed by MRI of the brain with and without contrast within 30 days prior to the initiation of injections of VBI-1901. An initial therapy requires surgery and radiation therapy, with or without temozolomide. In addition, alternate therapy (with or instead of temozolomide) is permitted as part of initial therapy.
  4. Recovery from the effects of surgery.
  5. Corticosteroid (dexamethasone or equivalent) dosage ≤ 4mg daily that has been stable or decreasing for at least 5 days.
  6. Recovery from prior therapy toxicity defined as resolution of all treatment-related adverse events (AEs) to Grade ≤ 1 or pre-treatment baseline (except alopecia).
  7. Karnofsky performance status (KPS) score ≥ 70%.
  8. Adequate organ function, including the following:

    1. Absolute neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 100,000/μL
    2. Serum creatinine < 1.5 × the upper limit of normal (ULN)
    3. Bilirubin < 1.5 × ULN
    4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN
  9. Women of childbearing potential: negative urine pregnancy test within 14 days prior to the start of VBI-1901 treatment.
  10. Female subjects of childbearing potential and sexually active male subjects must agree to use an acceptable form of contraception for heterosexual activity (i.e., oral contraceptives, double barrier methods, hormonal injectable, transdermal, or implanted contraceptives, tubal ligation, or vasectomy of their sexual partner(s) for >30 days before Screening, during the study, and for 60 days after the last dose of study drug).
  11. Female subjects without childbearing potential (spontaneous amenorrhea for > 12 months or surgically sterilized by tubal ligation, hysterectomy, or bilateral oophorectomy > 6 months before Screening) are eligible for inclusion without contraceptive use restriction.
  12. Able and willing to comply with protocol requirements in the opinion of the Investigator, including being able to have an MRI.
  13. Written consent has been obtained.
  14. Tumor specimen available for central pathological review.

Exclusion Criteria: Part A Dose Escalation

  1. Contrast-enhancing residual tumor that is associated with either diffuse sub-ependymal or leptomeningeal dissemination.
  2. Requirement of systemic corticosteroid therapy > 4 mg/day of dexamethasone or equivalent or requirement of increasing dose of systemic corticosteroids during the 7 days prior to the start of VBI-1901 treatment.
  3. Evidence of HCMV viremia in serum of > 18,200 (4.3Log10) IU/mL using FDA approved COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).
  4. Surgical resection or major surgical procedure within 4 days prior to the start of VBI-1901, or stereotactic biopsy within 7 days prior to the start of VBI-1901.
  5. Active infection requiring intravenous antibiotics or antiviral.
  6. History of cancer (other than GBM or prostate) within the past 2 years that could negatively impact survival and/or potentially confound tumor response assessments within this study.
  7. Known immunosuppressive disease or active systemic autoimmune disease such as systemic lupus erythematosus, human immunodeficiency virus infection, Hepatitis B virus or Hepatitis C virus infections. Subjects with vitiligo, type 1 diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement therapy, psoriasis not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  8. Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.
  9. Evidence of intra-tumoral or peri-tumoral hemorrhage on baseline, other than those that are ≤Grade 1 and either post-operative or stable on at least 2 consecutive MRI scans.
  10. Any condition which in the investigator's opinion makes the subject unsuitable for study participation.
  11. Lack of family or social support structure that would preclude continued participation in the study.

PART B OPTIMAL DOSE

Inclusion Criteria: Part B Optimal Dose

  1. 18-70 years of age.
  2. Histologically confirmed WHO grade IV glioblastoma.
  3. Unequivocal evidence of a first tumor recurrence with measurable disease, of an area no greater than 400 mm2, which may include patients with resected first recurrence tumor after an initial treatment regimen (prior to enrollment on this study) consisting of surgical intervention (tumor resection) and radiation, with or without temozolomide chemotherapy (depending on the MGMT methylation status), as assessed by MRI of the brain with and without contrast within 30 days prior to the initiation of injections of VBI-1901. In addition, alternate chemotherapy (with or instead of temozolomide) is permitted as part of initial therapy.
  4. At least 12 weeks since radiotherapy treatment and/or 23 days after chemotherapy prior to first dose of VBI-1901.
  5. Recovery from the effects of surgery.
  6. Corticosteroid (dexamethasone or equivalent) dosage ≤ 4mg daily that has been stable or decreasing for at least 5 days.
  7. Recovery from prior therapy toxicity, defined as resolution of all treatment-related adverse events (AEs) to Grade ≤ 1 or pre-treatment baseline (except alopecia).
  8. Karnofsky performance status (KPS) score ≥ 70%.
  9. Adequate organ function, including the following:

    1. Absolute neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 100,000/μL; absolute lymphocyte count ≥ 500/uL;
    2. Serum creatinine < 1.5 × the upper limit of normal (ULN);
    3. Bilirubin < 1.5 × ULN;
    4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN.
  10. Women of childbearing potential must have a negative urine pregnancy test within 14 days prior to the start of VBI-1901 treatment.
  11. Female subjects of childbearing potential and sexually active male subjects must agree to use an acceptable form of contraception for heterosexual activity (i.e., oral contraceptives, double barrier methods, hormonal injectable, transdermal, or implanted contraceptives, tubal ligation, or vasectomy of their sexual partner(s) for > 30 days before Screening, during the study, and for 60 days after the last dose of study drug).
  12. Female subjects without childbearing potential (spontaneous amenorrhea for > 12 months or surgically sterilized by tubal ligation, hysterectomy, or bilateral oophorectomy > 6 months before Screening) are eligible for inclusion without contraceptive use restriction.
  13. Able and willing to comply with protocol requirements, in the opinion of the Investigator.
  14. Written consent has been obtained.
  15. Tumor specimen available for central pathological review.

Exclusion Criteria: Part B Optimal Dose

  1. Contrast-enhancing residual tumor that is any of the following:

    1. An area greater than 400mm2;
    2. Multi-focal (defined as two separate areas of contrast enhancement measuring at least 1 cm in 2 planes that are not contiguous on either fluid-attenuated inversion recovery (FLAIR) or T2 sequences);
    3. Associated with either diffuse sub-ependymal or leptomeningeal dissemination.
  2. IDH1/2 has been proven to be mutated by IHC or PCR or if recurrent GBM was previously a lower grade glioma and wildtype IDH1/2 status has not been confirmed.
  3. Requirement of systemic corticosteroid therapy > 4 mg/day of dexamethasone or equivalent or requirement of increasing dose of systemic corticosteroids during the 7 days prior to the start of VBI-1901 treatment.
  4. Evidence of HCMV viremia in plasma of >18,200 (4.3log10) IU/mL using FDA approved COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).
  5. Prior treatment involving immunotherapy, including oncolytic viruses, therapeutic vaccination, or biologics (e.g. monoclonal antibodies, such as bevacizumab) presumed to have immunomodulatory effects.
  6. Surgical resection or major surgical procedure within 14 days prior to the start of VBI-1901, or stereotactic biopsy within 14 days prior to the start of VBI-1901.
  7. Radiation therapy, local therapy (except for surgical re-resection), or systemic therapy following first recurrence/progressive disease. Excluded local therapies include stereotactic radiation boost, implantation of carmustine biodegradable wafers (Gliadel), intratumoral or convection- enhanced delivery administered agents, etc.
  8. Concurrent therapy with Optune® or use within 1 week of start of treatment with VBI-1901.
  9. Active infection requiring intravenous antibiotics or antivirals.
  10. History of cancer (other than GBM or prostate) within the past 2 years that has metastatic or local recurrence potential and could negatively impact survival and/or potentially confound tumor response assessments within this study.
  11. Known immunosuppressive disease or active systemic autoimmune disease such as systemic lupus erythematosus, human immunodeficiency virus infection, Hepatitis B virus or Hepatitis C virus infections. Subjects with vitiligo, type 1 diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement therapy, psoriasis not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  12. Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.
  13. Any severe adverse event or allergy suspected or attributed to the shingles vaccines that contains AS01B components.
  14. Evidence of intra- or peri-tumoral hemorrhage on baseline MRI scan, other than those that are ≤Grade 1 and either post-operative or stable on at least 2 consecutive MRI scans.
  15. Any condition which in the investigator's opinion makes the subject unsuitable for study participation.
  16. Lack of family or social support structure that would preclude continued participation in the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03382977
Other Study ID Numbers  ICMJE VBI-1901-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party VBI Vaccines Inc.
Study Sponsor  ICMJE VBI Vaccines Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Francisco Diaz-Mitoma, MD Variation Biotechnologies Inc.
PRS Account VBI Vaccines Inc.
Verification Date November 2020

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