Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults

Abstract

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 10(8) to 1 × 10(10) tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies.

Figure 1

Patient evaluation. Patients were evaluated for possible inclusion into the trial, enrolled, and treated with REOLYSIN as indicated in the accompanying flow diagram. A total of 18 patients were enrolled, and 15 were treated and received follow-up.

Figure 2

Pre, 6- and 12-month posttreatment MRI scans. Shown are contrast-enhanced MRI scans from patient 13 with a recurrent glioblastoma multiforme who underwent a 72-hour infusion with 1 × 10¹⁰ TCID₅₀ reovirus (highest dose tested). (a) MRI conducted at 6 months postinfusion, at formal end of trial, shows partial response compared to pre-entry MRI. (b) MRI conducted at 12 months postinfusion, on routine follow-up, and without any further antineoplastic therapy, shows a complete response compared to pre-entry MRI. MRI, magnetic resonance imaging; TCID₅₀, tissue culture infectious dose₅₀

Figure 3

Pre- and postinfusion MRIs. Shown are T2-weighted MRI preinfusion axial (a) and coronal (c) and 1-day postcompletion of infusion (postcatheter removal) axial (b) and coronal (d) from patient 13 (1 × 10¹⁰). Increased T2 signal is seen associated with cerebral edema produced by the underlying tumor preinfusion (see arrow). Postinfusion, there is a generalized increase in the T2 signal consistent with, but not proof of, convection of the agent. Due to the limitations of this study design and costs, direct labeling of the virus to confirm convection was not done. Such an increase in T2 signal could also be produced by inflammation related to local viral infection of tumor cells, but the uniform nature of the increased volume of T2 hyperintensity would still support an increased distribution of reovirus over simple inoculation. MRI, magnetic resonance imaging.

Figure 4

Catheter placement. Representative computed tomography showing a typical catheter placement. White arrow indicates catheter (white). Block arrow with black outline shows tumor, dark gray. Only a single catheter is visualized on this axial view as catheters were intentionally placed at opposite or at least distant poles of tumor to maximize virus distribution. Catheter placement was made by the neurosurgeon such that the virus would be delivered to the enhancing rim of the tumor as seen on postgadolinium magnetic resonance imaging.