NCT03382977终止1 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 70
- 试验地点
- 24
- 主要终点
- Occurrence of AEs during each treatment cycle
研究概览
简要总结
The purpose of this study is to assess the safety and tolerability of VBI-1901 in subjects with recurrent malignant gliomas (glioblastoma, or GBM).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
None, open-label Allocation (FDAAA)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •PART A DOSE ESCALATION
- •Inclusion Criteria: Part A Dose Escalation
- •18-70 years of age
- •Histologically confirmed WHO grade IV glioblastoma
- •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-
- •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.
- •Recovery from the effects of surgery.
- •Corticosteroid (dexamethasone or equivalent) dosage ≤ 4mg daily that has been stable or decreasing for at least 5 days.
- •Recovery from prior therapy toxicity defined as resolution of all treatment-related adverse events (AEs) to Grade ≤ 1 or pre-treatment baseline (except alopecia).
- •Karnofsky performance status (KPS) score ≥ 70%.
- •Adequate organ function, including the following:
- •Absolute neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 100,000/μL
- •Serum creatinine < 1.5 × the upper limit of normal (ULN)
- •Bilirubin < 1.5 × ULN
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN
- •Women of childbearing potential: negative urine pregnancy test within 14 days prior to the start of VBI-1901 treatment.
- •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).
- •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.
- •Able and willing to comply with protocol requirements in the opinion of the Investigator, including being able to have an MRI.
- •Written consent has been obtained.
- •Tumor specimen available for central pathological review.
排除标准
- •Part A Dose Escalation
- •Contrast-enhancing residual tumor that is associated with either diffuse sub-ependymal or leptomeningeal dissemination.
- •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.
- •Evidence of HCMV viremia in serum of > 18,200 (4.3Log10) IU/mL using FDA approved COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).
- •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-
- •Active infection requiring intravenous antibiotics or antiviral.
- •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.
- •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.
- •Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.
- •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.
- •Any condition which in the investigator's opinion makes the subject unsuitable for study participation.
- •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
- •18-70 years of age.
- •Histologically confirmed WHO grade IV glioblastoma.
- •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-
- •In addition, alternate chemotherapy (with or instead of temozolomide) is permitted as part of initial therapy.
- •At least 12 weeks since radiotherapy treatment and/or 23 days after chemotherapy prior to first dose of VBI-
- •Recovery from the effects of surgery.
- •Corticosteroid (dexamethasone or equivalent) dosage ≤ 4mg daily that has been stable or decreasing for at least 5 days.
- •Recovery from prior therapy toxicity, defined as resolution of all treatment-related adverse events (AEs) to Grade ≤ 1 or pre-treatment baseline (except alopecia).
- •Karnofsky performance status (KPS) score ≥ 70%.
- •Adequate organ function, including the following:
- •Absolute neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 100,000/μL; absolute lymphocyte count ≥ 500/uL;
- •Serum creatinine < 1.5 × the upper limit of normal (ULN);
- •Bilirubin < 1.5 × ULN;
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN.
- •Women of childbearing potential must have a negative urine pregnancy test within 14 days prior to the start of VBI-1901 treatment.
- •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).
- •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.
- •Able and willing to comply with protocol requirements, in the opinion of the Investigator.
- •Written consent has been obtained.
- •Tumor specimen available for central pathological review.
- •Exclusion Criteria: Part B Optimal Dose
- •Contrast-enhancing residual tumor that is any of the following:
- •An area greater than 400mm2;
- •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);
- •Associated with either diffuse sub-ependymal or leptomeningeal dissemination.
- •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.
- •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.
- •Evidence of HCMV viremia in plasma of >18,200 (4.3log10) IU/mL using FDA approved COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).
- •Prior treatment involving immunotherapy, including oncolytic viruses, therapeutic vaccination, or biologics (e.g. monoclonal antibodies, such as bevacizumab) presumed to have immunomodulatory effects.
- •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-
- •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.
- •Concurrent therapy with Optune® or use within 1 week of start of treatment with VBI-
- •Active infection requiring intravenous antibiotics or antivirals.
- •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.
- •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.
- •Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.
- 另有 44 项未显示
研究组 & 干预措施
Part B AS01B Adjuvant
Experimental
VBI-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
干预措施: VBI-1901 (Biological)
Part C Standard of Care Treatment
Active Comparator
Single-agent standard-of-care (SOC) treatment with either carmustine intravenously at a dose of 150 mg/m² or lomustine orally at a dose of 110 mg/m² (up to a maximum dose of 200 mg).
干预措施: Carmustine (Drug)
Part C VBI-1901 with GM-CSF Adjuvant
Experimental
VBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 mL volume, given in two equal ID injections.
干预措施: VBI-1901 (Biological)
Part A Dose Level 3
Experimental
VBI-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
干预措施: VBI-1901 (Biological)
Part A Dose Level 2
Experimental
VBI-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
干预措施: VBI-1901 (Biological)
Part B GM-CSF Adjuvant
Experimental
VBI-1901 10 μg HCMV pp65 formulated with GM-CSF (200 μg) in 0.2 to 0.4 mL volume, given in two to four equal ID injections.
干预措施: VBI-1901 (Biological)
Part A Dose Level 1
Experimental
VBI-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
干预措施: VBI-1901 (Biological)
Part C Standard of Care Treatment
Active Comparator
Single-agent standard-of-care (SOC) treatment with either carmustine intravenously at a dose of 150 mg/m² or lomustine orally at a dose of 110 mg/m² (up to a maximum dose of 200 mg).
干预措施: Lomustine (Drug)
结局指标
主要结局
Occurrence of AEs during each treatment cycle
时间窗: Through 28 days after each study vaccination
Dose limiting toxicity (DLT) occurring during Part A of the study
时间窗: Through 14 days after each study vaccination
次要结局
- Change in quality of life (QOL questionnaire) compared to baseline(Baseline to study completion, an average of 12 months)
- 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)
- 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)
- 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)
- Reduction in steroid use 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)
- Overall survival (OS)(6, 12, 18 and 24 months from date of first dose)
- 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)
- 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)
研究者
研究点 (24)
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