Multiple Intracerebral Doses of Neural Stem Cell-Based Virotherapy (NSC-CRAd-S-pk7) for the Treatment of Recurrent High-Grade Gliomas

A Phase I Study of Multiple Doses of Neural Stem Cell-Based Oncolytic Virotherapy (NSC-CRAd-S-pk7) Administered Intracerebrally to Patients With Recurrent High-Grade Gliomas

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.

Study Overview

• Status: Suspended
• Conditions: Currently Only Enrolling Glioblastoma Patients at First Recurrence
• Intervention / Treatment: Procedure: Resection; Biological: Neural Stem Cells-expressing CRAd-S-pk7

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Stanford, California, United States, 94305
      • Standford University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27109
      • Wake Forest University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (NSC-CRAd-S-pk7); 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 (depending on when they enroll in the study) via a catheter that was placed during surgery

Procedure: Resection; Undergo surgical resection; Other Names: Intracerebral administration of NSC-CRAd-S-pk7 via intracavitary catheter; Removal of CSF samples via a catheter placed in the lateral cerebral ventricle; Biological: Neural Stem Cells-expressing CRAd-S-pk7; Given intracerebrally; Other Names: CRAd-S-pk7 loaded NSCs; NSC-CRAd-S-pk7; NSC-CRAd-S-pk7 Virotherapeutic; NSCs loaded with CRAd-S-pk7; SC-CRAd-Survivin-pk7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Assessed using the Common Terminology Criteria for Adverse Events version 5.0.	Up to 30 days post removal of Rickhams
Progression-free survival (PFS)	Will estimate the rate 90% confidence interval (CI) for PFS at 6 months and use Kaplan Meier methods to estimate median PFS for all study participants as well as for the cohorts of glioblastoma (GBM) participants at first recurrence who will be treated with 4 doses of NSC-CRAd-S-pk7 given once a week or every two weeks.	From the time of surgery to the event date of progression, assessed at 6 months]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neural Stem Cells-expressing CRAd-S-pk7 (NSC-CRAd-S-pk7) immunogenicity		Up to 30 days post removal of Rickhams
Changes in tumor growth	Develop a biomathematical model for predicting tumor response to study treatment.	Baseline up to 2 years
NSC-CRAd-S-pk7 migration within the brain	Neural stem-cells and/or free viral particles will be assessed in samples of post-treatment tissue samples.	Up to 30 days post removal of Rickhams
NSC-CRAd-S-pk7 migration outside the brain	4. Neural stem-cells and/or free viral particles will be assessed in samples of CSF, peripheral blood, urine, oral and rectal mucosa (via swabbing), and skin at the injection site (also via swabbing).	Up to 30 days post removal of Rickhams
Disease response	Response Assessment in Neuro-Oncology Criteria will be used to assess response on brain magnetic resonance imaging in all study participants who receive at least 80% of the planned doses of study treatment. Disease response will be similarly assessed for the cohorts of GBM participants at first recurrence who will be treated with 4 doses of NSC-CRAD-S-pk7 once a week or every two weeks.	Up to 2 years
Overall survival (OS)	Will estimate the rate 90% CI for OS at 9 months and use Kaplan Meier methods to estimate median OS for all study participants as well as for the cohorts of GBM participants at first recurrence who will be treated with 4 doses of NSC-CRAd-S-pk7 once a week or every two weeks.	From time of surgery to date of death, assessed at 9 months
Changes in HSPG and survivin expression	Changes in survivin expression by immunohistochemistry IHC in pre- and post-treatment tissue to see if there is a relationship with disease response.	Baseline up to 2 years
Changes in immune cell populations	Changes in immune cell populations in the tumor microenvironment in pre- and post-treatment tumor tissue samples will be assessed by Vectra Spectral Imaging.	Baseline up to 2 years
Assessed using multiplex immunoassays in cerebrospinal fluid (CSF) samples and RNA-sequencing in CSF, peripheral blood, and tumor tissue samples.		Up to 30 days post removal of Rickhams

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jana L Portnow, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2023
• Primary Completion (Estimated): August 4, 2027
• Study Completion (Estimated): August 4, 2027

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: November 22, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): September 1, 2026
• Last Update Submitted That Met QC Criteria: August 31, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Recurrent glioblastoma, oncolytic virus, neural stem cells, first recurrence
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: 22338 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2022-10170 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No