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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 : Recruiting
First Posted : December 26, 2017
Last Update Posted : November 28, 2018
Sponsor:
Information provided by (Responsible Party):
VBI Vaccines Inc.

Brief Summary:
The purpose of this study is to assess the safety and tolerability of VBI-1901 in subjects with Recurrent GBM.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Biological: VBI-1901 Phase 1

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
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) to patients with recurrent GBM.

Masking: None (Open Label)
Masking Description: None, open-label Allocation (FDAAA)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 6, 2017
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Biological: VBI-1901
The vaccine is formulated with GM-CSF and administered intradermally (ID).

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
Biological: VBI-1901
The vaccine is formulated with GM-CSF and administered intradermally (ID).

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
Biological: VBI-1901
The vaccine is formulated with GM-CSF and administered intradermally (ID).




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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).

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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).

  10. 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Inclusion Criteria: Part B

  1. 18-70 years of age.
  2. Histologically confirmed WHO grade IV glioblastoma, and no IDH mutation found by either IHC and/or sequencing during or before screening.
  3. Unequivocal evidence of a first tumor recurrence with measurable disease, defined as 1 cm but no greater than 3 cm of enhancing tissue measured in 2 planes (axial, coronal, or sagittal) after an initial treatment regimen (prior to enrollment on this study) consisting of surgical intervention (tumor resection) and radiation, with or without temozolomide chemotherapy, as assessed by MRI of the brain with and without contrast within 30 days prior to the initiation of injections of VBI‐1901.
  4. At least 12 weeks since radiotherapy treatment 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;
    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

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

    1. Greater than 3 cm in 2 planes (axial, coronal, or sagittal);
    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. 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 plasma of >18,200 (4.3log10) IU/mL using FDA approved COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).
  4. Prior treatment involving immunotherapy, including oncolytic viruses, therapeutic vaccination, or biologics (e.g. monoclonal antibodies) presumed to have immunomodulatory effects.
  5. 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.
  6. 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.
  7. Active infection requiring intravenous antibiotics or antivirals.
  8. 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.
  9. 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.
  10. Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.
  11. 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.
  12. Any condition which in the investigator's opinion makes the subject unsuitable for study participation.
  13. Lack of family or social support structure that would preclude continued participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03382977


Contacts
Contact: Deseree Wong, BSc, MBA 416-626-2671 ext 4425 deseree.wong@veristat.com
Contact: Bebi Yassin-Rajkumar, MS 866-574-7034 BYassin-Rajkumar@vbivaccines.com

Locations
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Edwin Nunez       ENUNEZ2@mgh.harvard.edu   
Principal Investigator: Deborah Forst, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Nicole Devaney       NicoleD_Devaney@DFCI.HARVARD.EDU   
Principal Investigator: Patrick Wen, MD         
United States, New York
The Neurological Institute of New York Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Natalie Busby    212-305-8487    nb2718@cumc.columbia.edu   
Principal Investigator: Andrew B Lassman, MD         
Sponsors and Collaborators
VBI Vaccines Inc.
Investigators
Study Director: Francisco Diaz-Mitoma, MD Variation Biotechnologies Inc.

Responsible Party: VBI Vaccines Inc.
ClinicalTrials.gov Identifier: NCT03382977     History of Changes
Other Study ID Numbers: VBI-1901-01
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: November 28, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by VBI Vaccines Inc.:
GBM
Glioblastoma
eVLP
VBI-1901
vaccine
immunotherapy
CMV
CNS
Brain
Cancer

Additional relevant MeSH terms:
Vaccines
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Immunologic Factors
Physiological Effects of Drugs