Repeated Neural Stem Cell Based Virotherapy for Newly Diagnosed High Grade Glioma

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about the safety and feasibility of administering repeated doses of neural stem cell (NSC)-conditionally replicative adenovirus (CRAd)-survivin (S)-protomer (p)k7, in persons with newly diagnosed high grade glioma. The main questions it aims to answer are: whether multiple doses of NSC-CRAd-S-pk7 are safe and feasible how multiple doses of NSC-CRAd-S-pk7 influence tumor response, overall survival, time to tumor progression, and quality of life. Participants will: undergo a biopsy to confirm high grade glioma, then receive the first dose of NSC-CRAd-S-pk7 into the brain about 2 weeks later, undergo surgery to remove the tumor and receive the second dose of NSC-CRAd-S-pk7 into the brain start chemoradiation about 2 weeks after surgery, then about 2 weeks later, receive the 3rd dose of NSC-CRAd-S-pk7 into the brain four weeks later, at the end of chemoradiation, receive a fourth dose of NSC-CRAd-S-pk7 into the brain. after radiation is finished, receive standard of care chemotherapy and tumor-treating fields. Two additional doses of NSC-CRAd-S-pk7 will be given every 4 weeks. Every other patient enrolled will receive N-acetylcysteine amide (NACA), from registration until the day prior to surgery and the second dose of NSC-CRAd-S-pk7.

Detailed Description
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The treatment regimen contains 3 phases: Surgical phase: Patients undergo a biopsy and upon intraoperative confirmation of high grade glioma, NSC-CRAd-S-pk7 dose #1 will be injected into the biopsy site. Patients will undergo resection of the tumor 14 (+/- 3) days later, administration of second dose of the investigational product (NSC-CRAd-S-pk7 dose #2), and implantation of the catheter system. The investigational product will then be given monthly for a total of 6 doses (see below). Every other patient enrolled (beginning with the first patient) will also undergo oral administration of NACA (an over-the-counter drug that acts as a free radical scavenger and improves NSC viability) starting at registration until the day prior to surgical tumor resection and planned investigational product injection #2. Radiotherapy phase: After recovery from surgery (usually within 2 weeks), standard chemoradiotherapy will be initiated consisting of daily radiotherapy (2 Gy per fraction x 30 fractions) and concomitant temozolomide (TMZ) chemotherapy (75 mg/m2 daily from day 1 of RT until last day of RT). About 10-14 days into radiotherapy (= approx. 4 weeks after intraoperative dose #2), patients will be receiving NSC-CRAd-S-pk7 dose #3 through the previously implanted catheter system. This also marks the beginning of the formal dose-limiting toxicity (DLT) period, as this virus' survivin gene promoter is activated by the concomitant irradiation. Four weeks later, ie. at the end of radiotherapy dose #4 is administered as previously, provided no DLT toxicity has been observed and viral treatment related toxicities have returned to grade ≤ 2. Adjuvant (also called maintenance) phase: As per standard of care, approx. 4 weeks after end of radiotherapy, patients will start maintenance TMZ chemotherapy (150 - 200 mg/m2, daily x 5 every 28 days) and loco-regional treatment with alternating Tumor Treating Fields (TTFields, Optune®). NSC-CRAd-S-pk7 doses #5 and #6 will be administered concurrently (± 3 days) with adjuvant cycle 1 and 2 of TMZ.

Official Title
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A Phase I Study of Repeated Neural Stem Cell Based Virotherapy in Combination With N-Acetylcysteine Amid (NACA) and Standard Radiation and Chemotherapy for Newly Diagnosed High Grade Glioma

Conditions
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Glioma, Malignant, New Diagnosis Tumor

Intervention / Treatment
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* Biological: NSC-CRAd-S-pk7
* Dietary Supplement: N-acetylcysteine amide (NACA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of a high-grade glioma (WHO grade 3 or grade 4). Patients must have presumed high grade glioma (WHO grade 3 or 4) based on clinical and radiologic evaluation for registration. A pathologic confirmation of high grade glioma must be made at the time of stereotactic biopsy prior to NSC-CRAd-S-pk7 injection; if this is not possible, the injection will not be performed and the subject will no longer be eligible for the study). Tumor must be accessible for injection and must not be located in the brainstem or contained within the ventricular system. Planning to undergo standard radiation/chemotherapy. 18 years of age or older. Performance status (PS) must be WHO PS of < 2. Stable or decreasing dose of corticosteroids equivalent to ≤ 6 mg/day for the 5 days prior to inclusion Serum glutamic-oxaloacetic transaminase (SGOT or AST) < 3x upper limit of normal Serum creatinine < 2mg/dl Platelets > 100,000/mm3 and white blood cells (WBCs) > 3000/mm3 Exclusion Criteria: Prior or ongoing liver disease including known cirrhosis. Known hepatitis B or C infection, known HIV infection. Chronic use of immunosuppressive drugs (with exception of corticosteroids required for mass effect). Acute viral, bacterial or fungal infections requiring therapy. Pregnant or breast-feeding patients. Evidence of metastatic disease or other malignancy (except squamous or basal cell skin cancers). Prior radiation therapy to the brain or prior treatment for brain tumor.

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
Interventional Model Description: Both groups will receive up to 6 doses of NSC-CRAd-S-pk7 in addition to standard of care radiation and temozolomide. Every other patient enrolled (beginning with the first patient) will undergo oral administration of N-acetylcysteine amide (NACA).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NSC-CRAd-S-pk7<br>NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses. | Biological: NSC-CRAd-S-pk7<br>* NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses.<br>|
| Experimental: NSC-CRAd-S-pk7 + N-acetylcysteine amide (NACA)<br>NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with 1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses. In addition, N-acetylcysteine amide (NACA) 600 mg oral, is taken daily from registration to just prior to dose 2 of NSC-CRAd-S-pk7. | Biological: NSC-CRAd-S-pk7<br>* NSC-CRAd-S-pk7 1·50 x 10⁸ NSCs loaded with1·875 x viral particles administered intra-tumorally on Day 0 and Day 15, then every 4 weeks for up to 6 total doses.<br>Dietary Supplement: N-acetylcysteine amide (NACA)<br>* N-acetylcysteine amide (NACA) 600 mg oral, is taken daily from registration to just prior to dose 2 of NSC-CRAd-S-pk7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity of repeat NSC-CRAd-S-pk7 dosing | Determination of the dose limiting toxicity of repeated dosing of NSC-CRAd-S-pk7 | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response to therapy | Objective response to therapy as determined by Immune Response Assessment in Neuro-Oncology (iRANO) criteria | 5 years | 
| Overall survival | Overall survival time from the first study product injection to death | 5 years | 
| Progression-free survival | Time from the first study product injection to first confirmed disease progression as determined by objective tumor response | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Virotherapy, NSC-CRAd-S-pk7