Study of Neoantigen-specific Adoptive T Cell Therapy for Newly Diagnosed MGMT Negative Glioblastoma Multiforme (GBM)

Study Overview
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Brief Summary
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This randomized study is designed to compare the combination of TVI-Brain-1 immunotherapy and standard therapy compared to standard therapy alone as a treatment for newly diagnosed MGMT unmethylated glioblastoma patients. The patients' own cancer cells collected after surgery are combined into a vaccine to produce an immune response that significantly increases the number of cancer neoantigen-specific effector T cell precursors in the patient's body. These cancer neoantigen-specific T cells are harvested from the blood, subsequently stimulated and expanded, and infused back into the patient.

Detailed Description
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This randomized study is designed to compare the combination of TVI-Brain-1 immunotherapy and standard therapy compared to standard therapy alone as a treatment for newly diagnosed MGMT unmethylated glioblastoma patients. The general procedures include the collection and testing of cancer tissue samples after surgery and chemoradiation therapy (radiation and temozolomide). For the patients randomized into the investigational study treatment group, they will also receive two vaccinations created from their own cancer cells, undergo leukapheresis to collect immune T-cells from their blood, and transfer of those activated effector T-cells after chemoradiation therapy. All patients are followed with MRIs at follow-up visits.

Official Title
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Randomized Phase 2b Study of Safety And Efficacy Of TVI-Brain-1 Combined With Conformal Radiotherapy And Temozolomide Vs Standard Therapy In Newly Diagnosed MGMT Negative Glioblastoma Multiforme (GBM)

Conditions
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Glioblastoma Multiforme of Brain

Intervention / Treatment
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* Biological: TVI-Brain-1
* Procedure: Standard of Care
* Radiation: Radiotherapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed MGMT unmethylated glioblastoma multiforme (no prior treatment) Sufficient cancer tissue obtained to allow for manufacture of autologous cancer cell vaccines The attenuated autologous cancer cell product generated has satisfied the product release criteria as determined by the sponsor quality control department Medical history, physical examination and laboratory testing performed within approximately 7 days before enrollment revealing kidney and liver organ function within normal limits not currently receiving glucocorticoids and have been off glucocorticoids for at least 24 hours prior to vaccination as well as when they receive the T cell infusion. Patient function assessment (Karnofsky score is > 60) a life expectancy of > 12 weeks. Hemoglobin is > 10 g/dL (may be transfused) White blood cell count is > 3,000 cells/microliter (mcL) of blood. Platelet count is > 100,000 platelets per mcL of blood (transfusion independent) Lymphocyte count is > 1,000 cells/mcL of blood. Exclusion Criteria: another concomitant life-threatening disease (not including glioblastoma multiforme) a second malignancy that is not in remission as determined by the clinical investigator. Exception: squamous or basal cell carcinoma of the skin. requirement for treatment with glucocorticoids to control brain swelling presence of active autoimmune disease that is currently being actively treated. psychological, familial, sociological or geographical conditions that do not permit adequate medical follow-up and compliance with the study protocol. Current pregnancy or a plan to become pregnant within 1-year following the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care<br>Subjects will have standard surgery which will be followed approximately 5 weeks later by combined radiotherapy and chemotherapy consisting of temozolomide 75 mg/m2 dosed once daily beginning on the first day of radiotherapy and continuing until the final day of radiotherapy. Subjects will receive adjuvant temozolomide, and proceed with post therapy surveillance. | Procedure: Standard of Care<br>* Surgery for tumor removal or debulking to minimize tumor burden<br>Radiation: Radiotherapy<br>* Conformal radiotherapy consists of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks.<br>Drug: Temozolomide<br>* All Subjects receive 75 mg/m2 of temozolomide daily beginning on the first day of radiotherapy and continuing until the completion of radiotherapy. Standard of care Subjects will also receive adjuvant temozolomide .<br>* Other names: Chemotherapy;|
| Experimental: Interventional TVI-Brain-1 Autologous Vaccine and activated autologous blood-derived t cells<br>TVI-Brain-1 immunotherapy is integrated with radiation and temozolomide in the test group in the following manner: 1) Subjects undergo surgical resection of their cancer and are tapered off steroids. 2) Subjects receive the first vaccination of TVI-Brain-1 as soon as the laboratory prepared vaccine is available for use (approximately 7 - 14 days following surgery). 3) Subjects receive a second vaccination 7-10 days later. 4) Subjects are leukapheresed to obtain immune T cells for ex vivo-activation. 5) Subjects' T cells are stored frozen until after chemoradiotherapy is completed. 6) Following chemoradiotherapy Subjects are infused with activated effector T cells followed by a 10-day course of low-dose interleukin 2 (IL-2). 7) Subjects then proceed with post therapy surveillance. | Biological: TVI-Brain-1<br>* Attenuated autologous cancer cells and activated autologous blood-derived t cells<br>Procedure: Standard of Care<br>* Surgery for tumor removal or debulking to minimize tumor burden<br>Radiation: Radiotherapy<br>* Conformal radiotherapy consists of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks.<br>Drug: Temozolomide<br>* All Subjects receive 75 mg/m2 of temozolomide daily beginning on the first day of radiotherapy and continuing until the completion of radiotherapy. Standard of care Subjects will also receive adjuvant temozolomide .<br>* Other names: Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | All Subjects will be evaluated and contacted to evaluate their status | From date of randomization until the date of death from any cause assessed up to 24 months after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Time to progression is evaluated by review and analysis of serial MRI's taken at specific Time to progression is evaluated by review and analysis of serial MRI's taken at specific timepoints | From date of randomization until the date of first documented progression assessed up to 24 months after randomization |