Virus-Based Combination Therapy Promising In High-Grade Glioma

Preliminary findings support further assessment of the combination of Toca 511 (vocimagene amiretrorepvec) and Toca FC (extended-release 5-fluorocytosine) in high-grade glioma patients with recurrent disease

medwireNews: Phase I trial results suggest that patients with recurrent high-grade glioma could derive benefit from a virus-based combination therapy.

Toca 511 (vocimagene amiretrorepvec) is a nonlytic retroviral replicating vector that specifically infects cancer cells and delivers a gene encoding a yeast cytosine deaminase, which converts a subsequently administered prodrug Toca FC (extended-release 5-fluorocytosine) into the metabolically active 5-fluorouracil, explain the researchers.

They anticipate less toxicity with the investigational therapy than with systemic chemotherapy as generation of the cytotoxic drug is restricted to virus-infected tumour cells. Furthermore, the team believes that “[t]his also enables the immune system to remain intact, preserving the capacity to develop antitumor immune responses.”

This dose-escalation trial enrolled 45 patients with high-grade glioma who had disease recurrence after prior radiotherapy and temozolomide chemotherapy. Participants underwent surgical resection before receiving increasing doses of Toca 511 (from 1.4 × 107–4.8 × 109 transducing units) delivered into the walls of the resection cavity followed approximately 6 weeks later by treatment with Toca FC (doses ranging from 130–220 mg/kg per day) for 7 days every 4–8 weeks.

Two patients experienced dose-limiting toxicities – one patient in the cohort given Toca 511 at a dose of 1.5 x 108 transducing units and Toca FC 130 mg/kg per day and the other who received Toca FC at the same dose, but 1.5 x 109 transducing units of Toca 511.

A maximum tolerated dose could not be established, given the small number of dose-limiting toxicities, say Michael Vogelbaum, from Cleveland Clinic Foundation in Ohio, USA, and fellow investigators.

They add that the combination treatment shows “excellent tolerability”, with a more favourable safety profile than an external group of glioblastoma patients at first or second recurrence given lomustine in the control arm of a phase III trial. Specifically, treatment-related side effects of at least grade 3 occurred in 3.7% of a subgroup of 27 glioblastoma patients at first or second recurrence given the virus-based combination therapy, compared with 36.9% of 84 lomustine-treated patients.

The efficacy results were also promising, the team reports in Science Translational Medicine, with a median overall survival (OS) of 13.6 months and a 6-month OS rate of 87.9% for the 43 evaluable patients.

And again, when compared with the external controls, the subgroup of participants with glioblastoma at first or second recurrence had a significantly better median OS, at 13.6 versus 7.1 months, giving a hazard ratio of 0.45.

Reflecting on the external control group, Michael Vogelbaum et al write: “Although such a comparison does not overcome the lack of an internal control and randomized patient assignment, it is considered robust, reflecting a phase 3 clinical trial patient population and establishing comparability to the subjects receiving Toca 511 and Toca FC.”

And they believe that the OS improvement and favourable tolerability of Toca 511 plus Toca FC “support moving forward with this treatment regimen” and warrant confirmation in the phase II or III randomised trial setting.

References

Cloughesy TF, Landolfi J, Hogan DJ, et al. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med 2016; 8: 341ra75. doi: 10.1126/scitranslmed.aad9784

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