Clinical trial NCT03382977: Study to Evaluate Safety, Tolerability, and Optimal Dose of Candidate GBM Vaccine VBI-1901 in Recurrent GBM Subjects
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Glioblastoma Multiforme
Keywords: GBM
Glioblastoma
eVLP
VBI-1901
vaccine
immunotherapy
CMV
CNS
Brain
Cancer
Lead sponsor: VBI Vaccines Inc.
Sponsor class: INDUSTRY
First posted: 2017-12-26
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Dose limiting toxicity (DLT) occurring during Part A of the study
timeFrame: Through 14 days after each study vaccination
measure: Occurrence of AEs during each treatment cycle
timeFrame: Through 28 days after each study vaccination
Secondary outcomes:
measure: Serum antibody immune response
timeFrame: Baseline and 2 weeks after each dose of vaccine in Part A and Part B and every 3 months in Part C
measure: Cellular immune responses
timeFrame: Baseline and 2 weeks after each dose of vaccine in Part A and Part B and every 3 months in Part C
measure: Progression free survival (PFS)
timeFrame: From the date of first dose to date of progression or death, as well as at 6, 12, 18 and 24 months
measure: Overall survival (OS)
timeFrame: 6, 12, 18 and 24 months from date of first dose
measure: Median overall survival in Part A and Part B of the study
timeFrame: Date of first dose to date of death from any cause, assessed up to 18 months
measure: Reduction in steroid use compared to baseline
timeFrame: Baseline to study completion, an average of 12 months
measure: Change in quality of life (QOL questionnaire) compared to baseline
timeFrame: Baseline to study completion, an average of 12 months
measure: Tumor response rates (TRR) in Part C of the study
timeFrame: Baseline to study completion, an average of 12 months
measure: Safety and efficacy of VBI-1901 compared to standard of care (SOC) in Part C of study
timeFrame: Baseline to study completion, an average of 12 months
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles Neuro-Oncology Program
state: California
city: Stanford
country: United States
facility: Stanford
state: California
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ridgewood
country: United States
facility: The Valley Hospital - Neurosurgeons of New Jersey
state: New Jersey
city: New York
country: United States
facility: The Neurological Institute of New York Columbia University Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Providence - Swedish Medical Center
state: Washington
Study officials:
affiliation: Variation Biotechnologies Inc.
name: Francisco Diaz-Mitoma, MD
role: STUDY_DIRECTOR
References: