Abstract A085: Durable responses observed in recurrent high-grade glioma (rHGG) with Toca 511 and Toca FC treatment
Authors: Cloughesy Timothy F. , Landolfi Joseph , Vogelbaum Michael , Ostertag Derek , Elder Bradley , Carter Bob , Chen Clark C. , Kalkanis Steven , Kesari Santosh , Lai Albert , Lee Ian , Liau Linda , Mikkelsen Tom , Nghiemphu Leia , Piccioni David , Accomando William , Diago Oscar , Hogan Daniel , Jolly Douglas J. , Wood Katie , Gruber Harry , Das Asha , Walbert Tobias 
Published: August 2018

Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector. The vector infects human cells with selectivity for cancer cells because genome integration is dependent on cell division and viral replication is inhibited by innate and adaptive immune responses, defective in malignant tissues. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-Fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid-derived suppressor cells, and tumor-associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs, and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6-19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting &gt; 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended phase 2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

Citation Format: Timothy F. Cloughesy, Joseph Landolfi, Michael Vogelbaum, Derek Ostertag, Bradley Elder, Bob Carter, Clark C. Chen, Steven Kalkanis, Santosh Kesari, Albert Lai, Ian Lee, Linda Liau, Tom Mikkelsen, Leia Nghiemphu, David Piccioni, William Accomando, Oscar Diago, Daniel Hogan, Douglas J. Jolly, Katie Wood, Harry Gruber, Asha Das, Tobias Walbert. Durable responses observed in recurrent high-grade glioma (rHGG) with Toca 511 and Toca FC treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A085.