VB-111 in Surgically Accessible Recurrent/Progressive GBM

Study Overview
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Brief Summary
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This research study is studying a new viral cancer therapy, ofranergene obadenovec (VB-111), for recurrent or progressive glioblastoma (GBM), a brain tumor that is growing or progressing despite earlier treatment.

Detailed Description
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This is a randomized, controlled, blinded, phase II, surgical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether it works in treating a specific disease. Investigational means that the drug is being studied. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved this intervention for recurrent or progressive glioblastoma. In this research study, ofranergene obadenovec (VB-111) is the investigational drug being studied. VB-111 has been studied in lab experiments and in other types of cancer, and information from these studies suggest that it may be beneficial for recurrent or progressive glioblastoma. VB-111 works by targeting and damaging the blood vessels that grow and nourish cancerous tumors leading to tumor starvation. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. After enrollment, participants will be randomized into one of three study groups. Randomization means that participants are put into a group by chance. Neither the participant nor the research doctor will choose what group a participant will be in. In group A participants receive VB-111 before and after surgery. In group B participants receive VB-111 after surgery. In group C participants won't receive VB-111 but would receive standard of care. Treatment will be provided blindly, meaning participants do not know (are blinded as to) what treatment they are receiving to ensure that the results are not affected by a placebo effect (the power of suggestion). Participants will be given a study medication and it will contain either VB-111 or placebo (IV solution with no medicine). VBL Therapeutics is supporting this research study by providing funding for the research study and the study drug. Participants will be in this research study for as long as they do not have serious side effects and their disease does not get worse. It is expected that about 45 people will take part in this research study.

Official Title
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A Randomized, Controlled Phase II Surgical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters for the Viral Cancer Therapy Ofranergene Obadenovec (VB-111) in Patients With Surgically Accessible Recurrent/Progressive Glioblastoma

Conditions
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Glioblastoma, Recurrent Glioblastoma

Intervention / Treatment
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* Drug: VB11
* Procedure: Surgery
* Other: Placebo
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ° ± µ ™ ® Histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma). First or second progression of glioblastoma/gliosarcoma (according to RANO criteria) following standard of care treatment upon initial diagnosis with radiation. Measurable disease by RANO criteria at progression. The maximal tumor volume at baseline meets the following criteria as determined by a local site investigator or surgeon: Longest diameter ≤ 4CM. Surgically resectable disease at progression. An interval of the following durations prior to randomization: At least 28 days from prior surgical resection, or 7 days from stereotactic biopsy At least 12 weeks from prior radiotherapy, unless there is unequivocal histologic confirmation of tumor progression At least 23 days from prior chemotherapy At least 42 days from nitrosureas At least 42 days from other anti-tumor therapies (including vaccines) At least 28 days from any investigational agent NOTE: no wash-out period required from TTF. Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide. Corticosteroid use at or less than dexamethasone 2mg daily. Participants should be on a stable or decreasing dose for at least 7 days prior to randomization. Age ≥ 18 years on day of signing informed consent KPS ≥ 70% (see Appendix A) Adequate bone marrow, liver, and renal function according to the following criteria: Absolute neutrophil count ≥ 1,500 cells/mL   1.5 K/μL Platelets ≥ 100,000 cells/mL   100 K/μL Total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN Aspartate aminotransferase (AST) ≤ 2.0 x ULN Serum creatinine level ≤ ULN or creatinine clearance ≥ 50 mL/min for participants with creatinine levels above normal limits (calculated by the Cockcroft-Gault formula) Ability to understand and willingness to sign a written informed consent document Availability of 10 unstained formalin-fixed paraffin-embedded slides. MRI within 14 days prior to registration. NOTE: Due to the fact that the screening MRI will not be used for response purpose, participants may be registered if screening CT or MRI is > 14 days of registration if prospective approval is received from Overall PI Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (withor without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment if she is considered not of child bearing potential. Males and females of childbearing potential must utilize a standard contraception method throughout the trial and up to 120 days after the last dose of treatment on study. NOTE: Women of childbearing potential and men with female spouses of childbearing potential must agree to use two methods of reliable contraception simultaneously or to practice complete abstinence from heterosexual contact prior to study entry, while receiving treatment, and for 4 months after undergoing treatment. One method must include a highly effective method such as an intrauterine device, hormonal (birth control pills, injections or implants), tubal ligation or partner's vasectomy. The other method can be an additional hormonal therapy or barrier method such as a male condom, diaphragm or cervical cap. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately Exclusion Criteria: Current or planned participation in a study of an investigational agent or using an investigational device. Has tumor primarily localized to the brainstem or spinal cord Has presence of diffuse leptomeningeal disease or extracranial disease. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment Minor surgical procedure (e.g. stereotactic biopsy or shunt placement) within 7 days of first study treatment, placement of vascular access within 2 days of first study treatment Expected to have surgery other than the neurosurgical procedure intended for the GBM lesion during study treatment period Prior stereotactic radiotherapy (Note: those who have had biopsy proven tumor recurrence at a site of SRS treatment should be considered eligible if approved by the study central Investigator) Prior anti-angiogenic therapy including VEGF sequestering agents (i.e. bevacizumab, aflibercept, etc.) or VEGFR inhibitors (cedirinib, pazopanib, sunitinib, sorafenib, etc.) Prior administration of the study drug VB-111 Concomitant medication that may interfere with study results (e.g. immunosuppressive agents other than inhaled, topical or intra-articular steroids or a stable or decreasing dose of oral corticosteroids of up to <2 mg/day dexamethasone equivalent) Known active second malignancy. Exceptions include non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Participants are not considered to have currently active malignancy if they have completed anticancer therapy and have been disease free for greater than 2 years prior to screening Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of stroke or transient ischemic attack within 6 months prior to randomization Evidence of CNS hemorrhage CTCAE grade 2 or above on screening MRI Active cardiac disease within 6 months prior to randomization (i.e. acute coronary syndrome, unstable angina, New York Heart Association grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment) Significant vascular disease within 6 months prior to randomization (e.g. aortic aneurysm requiring surgical repair, peripheral arterial thrombosis, symptomatic peripheral vascular disease) History of venous thromboembolism CTCAE version 5.0 grade 3 or greater Known proliferative and/or vascular retinopathy Inadequately controlled hypertension (defined as systolic blood pressure > 150mmHg and/or diastolic blood pressure > 100mmHg) within 1 week of randomization History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 6 months of randomization. History of active gastrointestinal bleeding within 6 months prior to randomization. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation) Current or recent (within 10 days of study randomization) use of aspirin > 325mg/day, clopidogrel > 75mg/day or equivalent. Therapeutic or prophylactic use of anticoagulants is allowed Known liver disease (alcoholic, drug/toxin induced, genetic or autoimmune) History of gastrointestinal perforation or abscess Positive testing to any of the following viruses: HIV, HBV, HCV within the last 6 months. Exceptions include participants with serology positive for HBV indicating past exposure but without evidence of active infection (e.g. negative PCR) History of intracranial abscess within 6 months prior to randomization Serious non-healing wound, active ulcer, or untreated bone fracture Pregnant or breastfeeding participants

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Before and After Surgery<br>VB-111 will be administered intravenously at a pre-determined dose at 14-28 days prior to surgery. Upon recovering from surgery (within 28-35 days after surgery), participants will receive intravenous VB-111 every 6 weeks. Participants evidencing disease progression may initiate bevacizumab at a pre-determined dose as needed for supportive care and will continue with VB-111 infusions every 6 weeks until tumor growth is evidenced a two consecutive time points. | Drug: VB11<br>* Intravenously administered type of gene therapy that works by blocking the process of blood-vessel creation. Disrupting a cancer from growing blood vessels, might slow the growth of the cancer or shrink it.<br>* Other names: Ofranergene obadenovec;Procedure: Surgery<br>* Treatment of disease or injury by cutting, abrading, suturing, or otherwise physically changing body tissues and organs.<br>Drug: Bevacizumab<br>* A type of antibody, Bevacizumab is intravenously administered and works by binding to and disrupting the vascular endothelial growth factor (VEGF). VEGF is a signal protein produced by cells that stimulates the formation of blood vessels. By disrupting VEGF, Bevacizumab helps to prevent the growth and maintenance of tumor blood vessels.<br>* Other names: Avastin;|
| Experimental: After Surgery<br>Placebo (IV solution with no medicine) will be administered intravenously at a pre-determined dose at 14-28 days prior to surgery. Upon recovering from surgery (within 28-35 days after surgery), participants will receive intravenous VB-111 every 6 weeks. Participants evidencing disease progression may initiate bevacizumab at a pre-determined dose as needed for supportive care and will continue with VB-111 infusions every 6 weeks until tumor growth is evidenced a two consecutive time points. | Drug: VB11<br>* Intravenously administered type of gene therapy that works by blocking the process of blood-vessel creation. Disrupting a cancer from growing blood vessels, might slow the growth of the cancer or shrink it.<br>* Other names: Ofranergene obadenovec;Procedure: Surgery<br>* Treatment of disease or injury by cutting, abrading, suturing, or otherwise physically changing body tissues and organs.<br>Other: Placebo<br>* Intravenous solution that has no therapeutic effect, used as a control in testing investigational drug.<br>Drug: Bevacizumab<br>* A type of antibody, Bevacizumab is intravenously administered and works by binding to and disrupting the vascular endothelial growth factor (VEGF). VEGF is a signal protein produced by cells that stimulates the formation of blood vessels. By disrupting VEGF, Bevacizumab helps to prevent the growth and maintenance of tumor blood vessels.<br>* Other names: Avastin;|
| Experimental: After Surgery Standard of Care<br>Placebo (IV solution with no medicine) will be administered intravenously at a pre-determined dose at 14-28 days prior to surgery. Upon recovery from surgery, participants will receive standard of care treatment every 6 weeks until tumor growth is evidenced a two consecutive time points. | Procedure: Surgery<br>* Treatment of disease or injury by cutting, abrading, suturing, or otherwise physically changing body tissues and organs.<br>Other: Placebo<br>* Intravenous solution that has no therapeutic effect, used as a control in testing investigational drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor infiltrating T cell (TIL) density | Tumor infiltrating T cell (TIL) density is defined as the number of T lymphocytes per nucleated cell, and calculated by detailed sequencing of recombined T cell receptor sequences obtained from the tumor specimen gDNA. A two-sample t-test with tumor size stratification will be used to test the difference of tumor infiltrating T cell density between the two groups (Group A vs combined Group B+C). Data distribution will be examined prior to analysis. Data transformations will be performed as deemed appropriate. | 2 years | 
| Rate of Dose Limiting Toxicity | AEs graded using CTCAE version 5.0 criteria. Safety will be assessed by quantifying the toxicities and grades experienced by participants who have received VB-111, including serious adverse events (SAEs) All participants who receive at least one dose of VB-111/placebo will be evaluable for toxicity from the time of their first treatment. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month progression-free survival | Defined as the percentage of participants with progression-free survival at 6 months from surgery as defined by RANO. Recurrent/progressive GBM participants treated with VB-111 (Group A and Group B) compared to control (Group C), using RANO criteria | 6 months | 
| Overall Survival | OS, analyses will be conducted using historical comparison data which are available from a pooled analysis of Phase II experience in recurrent Grade IV gliomas who have undergone surgery either just prior to starting treatment or as part of. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Participants without efficacy evaluation data or without survival data will be censored at Day 1. For evaluation of the expansion of TCR clones, a two-sample T-test with Bonferroni adjustment will be used to compare the increase number of expanded TCR clones after VB-111 in Group A+B vs Group C. | time from randomization until death from any cause up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Recurrent Glioblastoma