SNO 2017 Highlights: Intravenous administration of Toca 511

Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue

Tobias Walbert of Henry Ford Hospital presented results of this phase 1 trial, which tested administration of the Toca 511 virus by intravenous injection.  Toca 511 is a retroviral replicating vector that transmits a gene to infected tumor cells.  This gene, cytosine deaminase (CD) causes the cell to convert orally administered Toca FC (an extended release version of 5-fluorocytosine) into the active chemotherapy agent 5-fluorouracil.  Following intravenous injection for 1, 3, or 5 days, tumors were resected and additional Toca 511 was injected into the tumor cavity walls.  This pre-resection intravenous administration allowed investigators to analyze tumor tissue for detection of cytosine deaminase (CD) within tumors.

17 patients were included in this trial.  14 of these patients (82%) had diagnoses of GBM and the remaining three had grade 3 gliomas.   47% were at first recurrence while 53% were at second or more recurrence.  

11 of 17 (65%) resected tumors were positive for cytosine deaminase, showing that intravenously administered Toca 511 successfully entered into tumors in the majority of cases. Analysis of resected tumor tissue following intravenous Toca 511 injection found that tumors with high T-cell infiltrate did not limit the ability of Toca 511 to enter tumor cells.  Conversely, the presence of immunosuppressive regulatory T-cells (Tregs) were also not required to allow entry of Toca 511 into tumor cells.  

The maximum tolerated dose of Toca 511 was not defined and grade 3 or higher adverse events were rare, occurring in only 3 patients (17.6%). 

Stable disease was achieved in 3 of 17 patients (17.6%) and late onset (>12 months after treatment) radiologic responses were seen in two of 17 patients (11.8%), consistent with an immunologic mechanism of action.  The responding patients were an IDH wild-type anaplastic astrocytoma patient at 3rd recurrence, whose response was noted on MRI 9 months after discontinuing Toca FC and was on no other anti-cancer therapy;  and an IDH1-mutant GBM patient at first recurrence who had onset of response 13 months after initiating Toca FC.  Complete response was eventually achieved in this patient, and response has lasted for 16 months and counting. This patient remains on Toca FC and no other anti-cancer therapy.  Median overall survival from trial entry for this group of 17 patients, 53% of whom were at second or more recurrence, is 13.6 months.

This trial is one of three phase 1 trials of Toca 511/ Toca FC for recurrent malignant glioma, which are all now closed to recruitment.  Currently recruiting patients is the Toca 6 trial for recurrent solid tumors, and the randomized phase 2/3 Toca 5 trial for recurrent malignant glioma, which has just reopened as of November 2017.  A phase 1 trial of Toca 511/ Toca FC for newly diagnosed malignant glioma (Toca 7) is scheduled to open in 2018.

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