Safety issues

This phase I trial studies the safety of giving multiple intracerebral doses of NSC-CRAd-S-pk7 to treat patients with glioblastoma at first recurrence. NSC-CRAd-S-pk7 consists of neural stem cells that can target glioblastoma cells and carry a virus, which can kill cancer cells. Giving multiple doses of NSC-CRAd-S-pk7 may kill more tumor cells.

PRIMARY OBJECTIVE:

I. Determine the recommended maximum tolerated number of cycles (MTC) of intracavitary (ICT) administered neural stem cell-expressing CRAd-S-pk7 (NSCCRAd-S-pk7) for phase II testing based on dose-limiting toxicities (DLTs), the overall toxicity profile, and activity in patients with recurrent high-grade glioma (HGG).

II. Describe and compare the weekly dosing schedule (Treatment Schedule 4) to an every 2 week dosing schedule (Treatment Schedule 4a) of intracerebrally administered NSC-CRAd-S-pk7 based on DLTs, the overall toxicity profile, and activity in patients with glioblastoma at first recurrence.

III. Determine the recommended phase 2 dose schedule based on the overall toxicity profile, and activity in patients with recurrent high grade gliomas

SECONDARY OBJECTIVES:

I. I. Assess for evidence of biologic activity (cytotoxicity and anti-tumor immune responses) in posttreatment tissue samples.

II. Assess for the presence of NSC and/or CRAd-S-pk7 in post-treatment tissue samples.

III. Assess for possible development of antibody and T cell responses to the NSCs and/or CRAd-S-pk7 in CSF and blood.

IV. Assess for evidence of possible migration of NSCs and/or CRAd-S-pk7 outside of the brain and if so, determine if viral shedding is occurring.

V. Determine the persistence and intracerebral distribution of the NSCs and/or CRAd-S-pk7 whenever permission is given to perform a brain autopsy on a study participant.

VI. Estimate the rates of disease response, progression-free survival at 6 months (PFS6mo) and overall survival at 9 months (OS9mo) for all study participants and separately for the cohorts of glioblastoma patients at first recurrence treated at the MTC administered once a week or every 2 weeks.

VII. Identify a molecular signature of vulnerability for predicting which glioma patients will benefit most from treatment with NSC-CRAd-S-pk7.

VIII. Describe and compare changes in immunosuppressive and immunostimulatory cytokines in CSF from study participants enrolled to Treatment Schedules 4 and 4a.

IX. Assess for the presence of exhausted T cell phenotypes in CSF samples and compare the degree of T cell exhaustion in study participants enrolled to Treatment Schedules 4 and 4a.

OUTLINE:

Patients undergo standard surgical resection, and during surgery the first dose of study agent is injected into the wall of the resection cavity. Patients then receive three additional doses every week or every two weeks via a catheter placed during surgery. A second catheter is placed in the cerebral ventricle to obtain serial samples of CSF for correlative studies. Two weeks after the last dose of study agent is administered, study participants undergo a second surgical procedure to remove the catheters and obtain post-treatment tissue samples for analysis.

FINANCIAL ASSISTANCE:

There is funding to help with the cost of transportation, lodging, and meals for participants who qualify for financial assistance.

Inclusion Criteria:

• Patient must be age >= 18 years

• Patient has a Karnofsky performance status of >= 70%

• Patient has a life expectancy of >= 3 months

  • When determining the maximum tolerated number of treatment cycles (MTC): patient has a histologically confirmed diagnosis of a grade 3 or 4 glioma (eg., glioblastoma, grade 4 astrocytoma, grade 3 astrocytoma, grade 3 oligodendroglioma). (This part of the study has been completed).
  • When enrolling to Treatment Schedules 4 and 4a: patient has glioblastoma at first recurrence.

• Imaging studies show evidence of recurrent, supratentorial tumor(s).

• Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide

• The patient must be in need of surgery for tumor resection

• Based on the neurosurgeon's judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles

• Absolute neutrophil count (ANC) of >= 1000 cells/mm^3

• Platelet count >= 100,000 cells/mm^3

• Total bilirubin =< 2.0 mg/dl

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times the institutional upper limit of normal

• Serum creatinine =< the institutional upper limit of normal

• At least 2 weeks from taking the last dose of a targeted agent

• At least 4 weeks from the last dose of bevacizumab For temozolomide, an interval of 23 days is required from the last dose administered if the patient was recently treated with adjuvant temozolomide, consisting of temozolomide daily for 5 days, repeated every 28 days.

• At least 2 weeks from taking the last dose of a targeted agent.

• At least 4 weeks from the last dose of bevacizumab.

• All significant toxicities from previous anticancer therapy must have stabilized to a new baseline or resolved.

• All participants must have the ability to understand and the willingness to sign a written informed consent.

• The effects of this treatment on a developing fetus are unknown. Therefore, female patients of childbearing potential and sexually-active male patients or who are able to impregnate their partner, must agree to use an effective method of contraception while participating in this study. Patients of childbearing potential must have a negative pregnancy test =< 2 week prior to registration.

Exclusion Criteria:

• Patient has multi-focal disease.
• Patient is receiving radiation, chemotherapy, or another investigational agent.
• Patient has had prior therapy with neural stem cells.
• Patient has not recovered from any toxicity (> grade 1) of prior therapies, except alopecia.
• Patient is unable to undergo a brain MRI.
• Patient has chronic or active viral infections of the central nervous system (CNS).
• Patient has a coagulopathy or bleeding disorder.
• Patient has an uncontrolled illness including ongoing or active infection.
• Patient has another active malignancy.
• Patient is pregnant or breastfeeding.
• A patient has a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol.