repeated neural stem cell based virotherapy for newly diagnosed high grade glioma

Conditions: Glioma, Malignant; New Diagnosis Tumor

Summary: 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.

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.

Eligibility criteria:
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.

Keywords: virotherapy nsc-crad-s-pk7