Background. Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results. Among 56 patients, durable complete responses were observed. A subgroup was identified based onToca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions. Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.
Bibliographical noteFunding Information:
The authors thank the ABC2 Foundation, the National Brain Tumor Society, the American Brain Tumor Association, the Musella Foundation, and Voices Against Brain Cancer for their support and collaborations. N.K. was also supported in part by U01NS059821 from the National Institute of Neurological Diseases and Stroke.
Conflict of interest statement. D.O., W.A., O.R.D., D.J.H., D.G., T.K., D.J.J., H.E.G., and A.D. are employees and/or shareholders of Tocagen. N.K. is a consultant, has ownership interest in, and is the recipient of a research grant from Tocagen. T.W. and J.L. are advisers for Novocure. L.M.L. is an adviser for Genentech/Roche; M.A.V. is an adviser with Infuseon Therapeutics. T.F.C. is a paid consultant for Tocagen.
- Durable response rate
- Gene therapy
- Recurrent high grade glioma