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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03382977
Recruitment Status : Active, not recruiting
First Posted : December 26, 2017
Last Update Posted : July 1, 2022
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 malignant gliomas (glioblastoma, or GBM).

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Biological: VBI-1901 Drug: Carmustine Drug: Lomustine Phase 1 Phase 2

Detailed Description:
This is a three-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 and comparison with standard of care (SOC) treatment. Subjects in groups receiving VBI-1901 vaccination will continue to receive vaccine every 4 weeks until tumor progression per immunotherapy Response Assessment for Neuro-Oncology (iRANO)/Response Assessment for Neuro-Oncology (RANO) criteria.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 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 adjuvant and administered intradermally (ID) or with 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
Official Title: A Three-part, Phase I/II 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 : July 2025
Estimated Study Completion Date : August 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vaccines

Arm Intervention/treatment
Experimental: Part A 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 adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Experimental: Part A 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 adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Experimental: Part A 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 adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Experimental: Part B GM-CSF Adjuvant
VBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 to 0.4 mL volume, given in two to four equal ID injections.
Biological: VBI-1901
The vaccine is formulated with GM-CSF adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Experimental: Part B AS01B Adjuvant
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
Biological: VBI-1901
The vaccine is formulated with GM-CSF adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Experimental: Part C VBI-1901 with GM-CSF Adjuvant
VBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 to 0.4 mL volume, given in two to four equal ID injections.
Biological: VBI-1901
The vaccine is formulated with GM-CSF adjuvant and administered intradermally (ID) or with AS01B adjuvant and administered intramuscularly (IM) to patients with recurrent GBM.

Active Comparator: Part C Standard of Care Treatment
Single-agent standard-of-care (SOC) treatment with either carmustine intravenously at a dose of 150 mg/m² or lomustine orally at a dose of 110 mg/m² (up to a maximum dose of 200 mg).
Drug: Carmustine
Treatment with carmustine intravenously at a dose of 150 mg/m² on Day 1 and every 6 weeks until the earlier of disease progression or intolerable toxicity.
Other Name: BiCNU

Drug: Lomustine
Treatment with lomustine given orally at a dose of 110 mg/m² (up to a maximum dose of 200 mg) on Day 1 and every 6 weeks until the earlier of disease progression or intolerable toxicity.
Other Name: Gleostine




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) occurring during Part A of the study [ Time Frame: Through 14 days after each study vaccination ]
  2. Occurrence of AEs during each treatment cycle [ Time Frame: Through 28 days after each study vaccination ]

Secondary Outcome Measures :
  1. Serum antibody immune response [ Time Frame: Baseline and 2 weeks after each dose of vaccine in Part A and Part B and every 3 months in Part C ]
    Assessment of IgG antibody to HCMV gB antigen by ELISA

  2. Cellular immune responses [ Time Frame: Baseline and 2 weeks after each dose of vaccine in Part A and Part B and every 3 months in Part C ]
    Assessment of IFN-γ and IL-5 positive peripheral blood mononuclear cells by ELISPOT

  3. Progression free survival (PFS) [ Time Frame: From the date of first dose to date of progression or death, as well as at 6, 12, 18 and 24 months ]
    Progression free survival (PFS) from date of first dose to date of progression (per iRANO/RANO criteria) or death, as well as at 6, 12, 18 and 24 months.

  4. Overall survival (OS) [ Time Frame: 6, 12, 18 and 24 months from date of first dose ]
  5. Median overall survival in Part A and Part B of the study [ Time Frame: Date of first dose to date of death from any cause, assessed up to 18 months ]
  6. Reduction in steroid use compared to baseline [ Time Frame: Baseline to study completion, an average of 12 months ]
  7. Change in quality of life (QOL questionnaire) compared to baseline [ Time Frame: Baseline to study completion, an average of 12 months ]
  8. Tumor response rates (TRR) in Part C of the study [ Time Frame: Baseline to study completion, an average of 12 months ]
    Complete response rate, partial response rate, progressive disease and stable disease

  9. Safety and efficacy of VBI-1901 compared to standard of care (SOC) in Part C of study [ Time Frame: Baseline to study completion, an average of 12 months ]
    An integrated analysis of safety and efficacy (OS, TRR, PFS) in subjects receiving VBI-1901 at 10 µg dose formulated with GM-CSF as compared to subjects receiving SOC



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (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 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.

PART C RANDOMIZED OPEN-LABEL STUDY EXTENSION

Inclusion Criteria: Part C Randomized Open-label Study Extension

  1. 18 years of age or older.
  2. Histologically confirmed WHO grade IV glioblastoma.
  3. Unequivocal evidence of a first tumor recurrence with measurable disease of an area no greater than 600 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 the start of study treatment.
  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 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 > 40 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.

Exclusion Criteria: Part C Randomized Open-label Study Extension

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

    1. An area greater than 600 mm2;
    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 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) or, other qualified HCMV assay.
  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 the study treatment, or stereotactic biopsy within 7 days prior to the start of treatment.
  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 study treatment.
  13. 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.
  14. Any condition which in the investigator's opinion makes the subject unsuitable for study participation.
  15. 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


Locations
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United States, California
University of California, Los Angeles Neuro-Oncology Program
Los Angeles, California, United States, 90095
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New York
The Neurological Institute of New York Columbia University Medical Center
New York, New York, United States, 10032
Sponsors and Collaborators
VBI Vaccines Inc.
Investigators
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Study Director: Francisco Diaz-Mitoma, MD Variation Biotechnologies Inc.
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Responsible Party: VBI Vaccines Inc.
ClinicalTrials.gov Identifier: NCT03382977    
Other Study ID Numbers: VBI-1901-01
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: July 1, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Carmustine
Lomustine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents