High-grade gliomas (HGGs), including glioblastoma multiforme (GBM), are not effectively treated with current therapies. Cloughesy et al1recently reported the results of a phase 1 clinical trial treating patients with recurrent HGG with a novel combination of Toca 511 (vocimagene amiretrorepvec) followed by Toca FC (extended release 5-fluorocytosine).
Toca 511 is an investigational nonlytic, retroviral replicating vector surgically injected into the walls of tumor resection cavities to deliver a yeast cytosine deaminase gene to replicating cells. Cytosine deaminase expresses an enzyme that converts the prodrug Toca FC (extended-release version of 5-fluorocytosine) to 5-fluorouracil (5-FU). Usually, 5-FU chemotherapy is inefficient at crossing the blood-brain barrier, but the combination of Toca 511 and Toca FC solves this problem because conversion to 5-FU occurs after 5-fluorocytosine has already crossed the blood-brain barrier into Toca 511–infected cells. Because this retroviral replicating vector was designed to depend on cell division for genome integration, it preferentially infects replicating cancer and nearby immune cells; in addition, systemic side effects are minimized because of the short 5-FU half-life and direct Toca 511 injection to infect tumor cells. To test safety and efficacy, Cloughesy et al administered increasing doses of Toca 511 to 45 subjects after surgical resection, followed by Toca FC administration for 7 days every 4 to 8 weeks until radiological tumor progression or clinical progression. These subjects were compared with an external control of subjects receiving standard therapy with lomustine for recurrent HGG. Subjects were divided into cohorts receiving either higher (cohorts 4-7a) or lower (cohorts 1-3) doses of Toca 511, with overall survival (OS) also compared between the 2 groups. There was a trend observed for dose response in OS of 14.4 months for the higher-dose cohort relative to the 11.8 months OS for the lower-dose cohort (Figure, A). Likewise, the OS of subjects receiving Toca 511 and Toca FC was 13.6 months compared with 7.1 months for the lomustine control (Figure, B). OS from initial diagnosis of patients with GBM at the first or second recurrence was 29.2 months compared with 21.3 months in the control group (Figure, C). Few adverse events were reported during the course of the study, and there were no treatment-related deaths. There were also fewer treatment-emergent grade ≥ 3 adverse events relative to the lomustine control, indicating that the Toca 511/Toca FC treatment course has a more favorable safety profile.
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