Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

Abstract

Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

“…While this is an abysmal outlook for patients many efforts are underway to improve survival, with recent data suggesting promising results with novel combinatorial therapies (42,43). TMZ is the current standard-of-care chemotherapy agent employed in the clinic for GBM patients, but its effect on median patient survival is relatively small (increased 2 months).…”

Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

“…This treatment regimen has shown favorable safety and tolerability profiles in addition to durable responses associated with shrinkage and stable disease by independent radiologic review of serial MRI brain scans in patients receiving higher doses of Toca 511 in phase 1 trials. Patients showed durable survival advantages compared to historical controls, especially in those with radiologic responses and stable disease 2 . Toca 511 in combination with Toca FC is currently under investigation in an international, multicenter, randomized phase 2/3 trial in patients with recurrent high grade glioma (NCT02414165).…”

MethylMeter ® : Bisulfite-Free Quantitative and Sensitive DNA Methylation Profiling and Mutation Detection in FFPE Samples

“…A second MGMT validation was performed focusing on a set of 26 recurrent high-grade GBM tumors from frozen tumor tissue for which mRNA expression data were also obtained [41]. These samples were previously analyzed for MGMT methylation by undisclosed methods at multiple clinical study centers.…”