Phase I Study of Replication-Competent Adenovirus-Mediated Double Suicide Gene Therapy With Stereotactic Radiosurgery in Patients With Recurrent or Progressive High Grade Astrocytomas
Overview
- Phase
- Phase 1
- Intervention
- Ad5-yCD/mutTKSR39rep-ADP adenovirus and fractionated stereotactic radiosurgery (fSRS)
- Conditions
- Malignant Glioma of Brain
- Sponsor
- Henry Ford Health System
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
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.
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.
Investigators
Tobias Walbert, MD, PhD
Principal Investigator
Henry Ford Health System
Eligibility Criteria
Inclusion Criteria
- •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
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.
Arms & Interventions
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.
Intervention: Ad5-yCD/mutTKSR39rep-ADP adenovirus and fractionated stereotactic radiosurgery (fSRS)
Outcomes
Primary Outcomes
Maximum Tolerated Dose
Time Frame: 30 days
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.
Secondary Outcomes
- Assessment of antitumor immune response by using antibodies against surface markers(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(Pre-surgery (day 0), 3, 7, 14, 21, 30, 90 days.)
- 1. Assessment of antitumor immune response(Pre-surgery (day 0), 3, 7, 14, 21, 30, 90 days.)