3+ 3 Dose Escalation

Therapeutic Vaccine: VBI-1901

The vaccine is formulated with GM-CSF and administered intradermally (ID) to patients with recurrent GBM.

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) consisting of surgical intervention (tumor resection), radiation, and temozolomide chemotherapy (per Stupp protocol), as assessed by MRI of the brain with and without contrast within 30 days prior to the initiation of injections of VBI-1901.
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, including being able to have an MRI in the opinion of the Investigator.
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.
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), radiation, and temozolomide chemotherapy (per Stupp protocol), 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 treatment per Stupp protocol 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.