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

NCT03382977

Description:

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

Related Conditions:
  • Glioblastoma
  • Glioblastoma, IDH-Wildtype
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: VBI-1901-01
  • NCT ID: NCT03382977

Conditions

  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
VBI-1901Dose Level 1

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1ExperimentalVBI-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
  • VBI-1901
Dose Level 2ExperimentalVBI-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
  • VBI-1901
Dose Level 3ExperimentalVBI-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
  • VBI-1901
Dose Level 4ExperimentalVBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal ID injections.
  • VBI-1901
Dose Level 5ExperimentalVBI-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
  • VBI-1901

Eligibility 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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Dose limiting toxicity (DLT) occurring during Part A and the occurrence of AEs in Part A and B of the study

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Serum IgG anti-gB antibody titers in baseline and post vaccination samples.
Measure:Cellular immunity against HCMV gB and pp65 antigens (Part A and B)
Time Frame:Baseline and 2 weeks after each dose of vaccine
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Additional exploratory immunological measurements, including changes in the frequency of myeloid suppressor cells and regulatory T cells (Tregs)
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival (OS) (Part A and B)
Time Frame:6 months and 12 months from date of first dose
Safety Issue:
Description:Overall survival (OS) at 6 months and 12 months from date of first dose
Measure: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
Safety Issue:
Description:Median overall survival
Measure:Reduction in steroid use compared to baseline (Part A and B)
Time Frame:Baseline to study completion, an average of 12 months
Safety Issue:
Description:Reduction in steroid use compared to baseline
Measure: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
Safety Issue:
Description:Change in quality of life (QOL questionnaire) compared to baseline
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:VBI Vaccines Inc.

Trial Keywords

  • GBM
  • Glioblastoma
  • eVLP
  • VBI-1901
  • vaccine
  • immunotherapy
  • CMV
  • CNS
  • Brain
  • Cancer

Last Updated

November 29, 2019