Adenovirus Mediated Suicide Gene Therapy With Radiotherapy in Progressive Astrocytoma.

Phase I Study of Replication-Competent Adenovirus-Mediated Double Suicide Gene Therapy With Stereotactic Radiosurgery in Patients With Recurrent or Progressive High Grade Astrocytomas

The primary goal of this Phase I study is to determine the maximum tolerated dose of oncolytic adenovirus mediated double suicide-gene therapy in combination with fractionated stereotactic radiosurgery in patients with recurrent high-grade astrocytoma undergoing resection.

Study Overview

• Status: Recruiting
• Conditions: Glioma; Glioblastoma; Astrocytoma; Malignant Glioma of Brain; Brain Cancer; Brain Tumor; Glioblastoma Multiforme; GBM; Malignant Astrocytoma
• Intervention / Treatment: Biological: Ad5-yCD/mutTKSR39rep-ADP adenovirus and fractionated stereotactic radiosurgery (fSRS)

Detailed Description

Detailed study description:

Patients with recurrent glioblastoma (GBM) or progressive high grade astrocytoma who are scheduled to undergo repeat surgery are eligible. After the removal of as much tumor tissue as possible, a modified oncolytic adenovirus is injected into the wall of the resection cavity and any residual tumor tissue. The goal of this study is to determine the maximum tolerated dose (MTD) of the injected adenovirus. This treatment is combined with a combination of oral 5-fluorocytosine (5-FC) and valganciclovir (vGCV) prodrug therapy. Following the surgery, patients will be treated with fractionated radiosurgery (fSRS). Patients will be monitored for 30 days before they start on next line anti-cancer therapy.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tobias Walbert, MD, PhD; Phone Number: 3139162723; Email: twalber1@hfhs.org
• Study Contact Backup: Name: Nyati Shyam, PhD; Phone Number: 734-272-1751; Email: snyati1@hfhs.org

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Health System
      • Contact: Tobias Walbert, MD, PhD; Phone Number: 3139162723; Email: twalber1@hfhs.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Subjects with radiologic evidence of intracranial recurrence or progression of a previously diagnosed high-grade astrocytoma.

   To be eligible for this trial, the subjects must have:

   • Histologically documented glioblastomas or anaplastic astrocytoma prior to the debulking surgery that is suspicious to have progressed on imaging. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation while at least 4 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen.
   • Patients must be ≥ 18 years of age, able to provide informed consent and express a willingness to meet all the expected requirements of the protocol for the duration of the study.
   • Must have recovered from toxicity (grade 2 or less) of prior therapy.
   • Eligible for partial or total resection of the recurrent tumor
   • No anticipated physical connection between post-resection tumor cavity and cerebral ventricle
   • Karnofsky performance status (KPS) ≥ 60 at time of surgery
   • No prior treatment of the tumor with gene or virus therapy, immunotherapy, brachytherapy, or implants of polymers containing chemotherapeutic agents (e.g. Gliadel Wafer)
   • No immunosuppressive or immune disorder
   • Baseline organ function testing intact
   • Patients who are candidates for surgical debulking (re-resection) following recurrence of diseases based on multidisciplinary evaluation by neurosurgeons, radiation oncologists, neuro-radiologists, and neuro-oncologists.

2. Subjects must have adequate baseline organ function, as assessed by the following laboratory values, within 30 days before initiating the study therapy:

   • Adequate renal function with creatinine clearance ≥ 50 mL/min/m2
   • Platelet count ≥ 100,000/μL
   • Absolute neutrophil count ≥ 1,000/μL
   • Hemoglobin > 10.0 g/dL
   • Bilirubin < 1.5 mg/dL; SGOT and SGPT < 2.5 times upper limit of normal (ULN).
3. Women of child-bearing potential will be required to practice birth control for the duration of the treatment and for at least 90 days after surgery with intratumor virus inoculation. Men must use barrier protection for the duration of treatment and for at least 90 days after surgery with intratumor virus inoculation treatment.

Exclusion Criteria:

• Acute infection. Acute infection is defined by any viral, bacterial, or fungal infection that has required active treatment and caused oral temperature >38.5oC and/or clinically significant leukocytosis
• Serum antibodies to human immunodeficiency virus (HIV)
• Previous history of liver disease including autoimmune or viral hepatitis
• Positive serologic test for Hepatitis B or C at baseline
• Immunosuppressive therapy except for corticosteroid use
• Serious medical or psychiatric illness or concomitant medication, which, in the judgment of the investigator, might interfere with the subject's ability to respond to or tolerate the treatment or complete the trial
• Impaired immunity or susceptibility to serious viral infections
• Pregnant or lactating females
• Allergy to any product used on the protocol
• Patient is not able to undergo a brain MRI.
• Patients who are not eligible for debulking surgery or resection of recurrent disease will be considered ineligible.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ad5-yCD/mutTKSR39rep-ADP adenovirus and fSRS Arm; Subjects will receive a single intratumoral injection of the Ad5-yCD/mutTKSR39rep-ADP adenovirus at one of three dose levels beginning at 1 x 1011 vp and escalating in half-log (3-fold) increments to 1 x 1012 vp, along with the same dose of fractionated stereotactic radiosurgery until unacceptable toxicity, disease progression, or withdrawal of consent.

Biological: Ad5-yCD/mutTKSR39rep-ADP adenovirus and fractionated stereotactic radiosurgery (fSRS); Ad5-yCD/mutTKSR39rep-ADP adenovirus will be injected intratumoral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose	The primary objective is to determine the maximum tolerated dose of injected of Ad5-yCD/mutTKSR39rep-ADP adenovirus into the resection cavity at the time of surgery.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Assessment of antitumor immune response	Assessment of antitumor immune response by serum levels of interferon-gamma (IFN-γ) measured by ELISA and will be described by pico-gram per milliliter (pg/mL).	Pre-surgery (day 0), 3, 7, 14, 21, 30, 90 days.
2. Assessment of change in antitumor immune response by peripheral blood monoclonal cell (PBMC) counts	Assessment of change in antitumor immune response by peripheral blood monoclonal cell (PBMC) counts measured by flow cytometry	Pre-surgery (day 0), 3, 7, 14, 21, 30, 90 days.
Assessment of antitumor immune response by using antibodies against surface markers	Assessment of antitumor immune response by using antibodies against surface markers (CD3, CD56, CD4, CD8, CD45, CD69).	Pre-surgery (day 0), 3, 7, 14, 21, 30, 90 days.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life as assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30	Assessment of quality of life (QOL) by using the European Organization for Research and Treatment of Cancer (EORTC) tools consisting of the EORTC QLQ-C30	Pre-surgery (day 0), 30 days, 90 days
Quality of life as assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20	Assessment of quality of life (QOL) by using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20	Pre-surgery (day 0), 30 days, 90 days

Collaborators and Investigators

• Sponsor: Henry Ford Health System
• Investigators: Principal Investigator: Tobias Walbert, MD, PhD, Henry Ford Health System

Publications and helpful links

General Publications

• Ene CI, Fueyo J, Lang FF. Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations. Neurosurg Focus. 2021 Feb;50(2):E6. doi: 10.3171/2020.11.FOCUS20853.
• Mitchell LA, Lopez Espinoza F, Mendoza D, Kato Y, Inagaki A, Hiraoka K, Kasahara N, Gruber HE, Jolly DJ, Robbins JM. Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro Oncol. 2017 Jul 1;19(7):930-939. doi: 10.1093/neuonc/nox037.
• Kiyokawa J, Wakimoto H. Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma. Oncolytic Virother. 2019 Oct 24;8:27-37. doi: 10.2147/OV.S196403. eCollection 2019.
• Oldfield EH, Ram Z, Culver KW, Blaese RM, DeVroom HL, Anderson WF. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther. 1993 Feb;4(1):39-69. doi: 10.1089/hum.1993.4.1-39.
• Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3054-7. doi: 10.1073/pnas.91.8.3054.
• Freytag SO, Rogulski KR, Paielli DL, Gilbert JD, Kim JH. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum Gene Ther. 1998 Jun 10;9(9):1323-33. doi: 10.1089/hum.1998.9.9-1323.

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 16, 2022
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 17, 2023

Study Record Updates

• Last Update Posted (Actual): December 16, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Glioblastoma; Glioma; Brain Neoplasms; Astrocytoma
• Other Study ID Numbers: HFHS-21-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No