Safety issues

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.

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).

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.

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.

No individual participant data (IPD) will be shared with other researchers.