Glioblastoma Multiforme
Conditions
Keywords
GBM, Glioblastoma, eVLP, VBI-1901, vaccine, immunotherapy, CMV, CNS, Brain, Cancer
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).
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.
Interventions
BIOLOGICALVBI-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.
DRUGCarmustine
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.
DRUGLomustine
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.
Sponsors
VBI Vaccines Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None, open-label Allocation (FDAAA)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose limiting toxicity (DLT) occurring during Part A of the study | Through 14 days after each study vaccination |
| Occurrence of AEs during each treatment cycle | Through 28 days after each study vaccination |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum antibody immune response | 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 |
| Cellular immune responses | 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 |
| Progression free survival (PFS) | 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. |
| Overall survival (OS) | 6, 12, 18 and 24 months from date of first dose | — |
| Median overall survival in Part A and Part B of the study | Date of first dose to date of death from any cause, assessed up to 18 months | — |
| Reduction in steroid use compared to baseline | Baseline to study completion, an average of 12 months | — |
| Change in quality of life (QOL questionnaire) compared to baseline | Baseline to study completion, an average of 12 months | — |
| Tumor response rates (TRR) in Part C of the study | Baseline to study completion, an average of 12 months | Complete response rate, partial response rate, progressive disease and stable disease |
| Safety and efficacy of VBI-1901 compared to standard of care (SOC) in Part C of study | 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 |
Countries
United States
Contacts
STUDY_DIRECTORFrancisco Diaz-Mitoma, MD
Variation Biotechnologies Inc.
Outcome results
None listed