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. 1. 18 years of age or older (no age upper limit).
2. Histologically confirmed supratentorial 2016 WHO classification grade IV Glioblastoma,
IDH-wildtype or grade 4 in the 2021 WHO classification. Tumors that are histologically
lower grade but are classified as glioblastoma using the WHO 2021 criteria because of
molecular alterations (TERT promoter mutation and/or EGFR amplification and/or
combined chromosome 7 gain/10 loss) are not eligible.
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 completed within 30 days prior to screening visit, if
not it should be performed as part of screening visit. In addition, alternate
bio/chemotherapy (with or instead of temozolomide) other than nitrosourea 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 or SOC treatment. Patients with recurrent GBM within 12
weeks of radiation therapy may be included if they have surgically proven tumor
recurrence (i.e.
this is proven to not be pseudoprogression).
5. Recovery from the effects of surgery.
6. Corticosteroid (dexamethasone or equivalent) dosage ≤ 2 mg daily that has been stable
for at least 5 days before randomization into the study.
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; CD4/CD8 ratio ≥1 or CD4 count ≥ 400/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 21
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:
1. Contrast-enhancing residual tumor that is any of the following:
1. An area greater than 600 mm2;
2. Multicentric (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. If recurrent GBM was previously a lower grade glioma and wildtype IDH1/2 status has
not been confirmed.
3. Requirement of systemic corticosteroid therapy > 2 mg/day of dexamethasone or
equivalent during the 5 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 presumed to have immunomodulatory effects. Prior bevacizumab
therapy is allowed, requiring at least 28 days washout period before randomization.
6. Surgical resection or major surgical procedure within 14 days prior to the start of
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 convectionenhanced delivery administered agents, etc.
8. More than 1 (one) line of prior chemotherapy (as an example, temozolomide given with
radiotherapy and after radiotherapy before recurrence is considered a single line).
9. Concurrent therapy with Optune® or use within 1 week of start of treatment. Previous
use of Optune® in the primary setting does not preclude participation in this clinical
trial.
10. Active infection requiring intravenous antibiotics or antivirals.
11. 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.
12. 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.
13. Any known allergies to the ingredients of VBI-1901 or GM-CSF or carmustine or
lomustine.
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 medical or social condition which in the investigator's opinion makes the subject
unsuitable for study participation. For instance, lack of family or social support
structure that would preclude continued participation in the study.
