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Clinical Trial
. 2016 Jun 1;8(341):341ra75.
doi: 10.1126/scitranslmed.aad9784.

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

Timothy F Cloughesy  1 , Joseph Landolfi  2 , Daniel J Hogan  3 , Stephen Bloomfield  2 , Bob Carter  4 , Clark C Chen  4 , J Bradley Elder  5 , Steven N Kalkanis  6 , Santosh Kesari  4 , Albert Lai  1 , Ian Y Lee  6 , Linda M Liau  1 , Tom Mikkelsen  6 , Phioanh Leia Nghiemphu  1 , David Piccioni  4 , Tobias Walbert  6 , Alice Chu  3 , Asha Das  3 , Oscar R Diago  3 , Dawn Gammon  3 , Harry E Gruber  3 , Michelle Hanna  7 , Douglas J Jolly  3 , Noriyuki Kasahara  8 , David McCarthy  9 , Leah Mitchell  3 , Derek Ostertag  3 , Joan M Robbins  3 , Maria Rodriguez-Aguirre  3 , Michael A Vogelbaum  10
Affiliations
Clinical Trial

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

Timothy F Cloughesy et al. Sci Transl Med. .

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).

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Figures

Fig. 1.
Fig. 1.. Overall Survival and Comparison of Toca 511 and Toca FC to Lomustine External Control
(A) The overall survival Kaplan-Meier plot of subjects who have received higher vs. lower doses Toca 511 and Toca FC. (B) The overall survival Kaplan-Meier plot of subjects with glioblastoma at first or second recurrence who received Toca 511 and Toca FC vs. the lomustine external control is shown. (C) The overall survival Kaplan-Meier plot from initial diagnosis of subjects with glioblastoma at first or second recurrence treated with Toca 511 and Toca FC vs. lomustine external control is shown.
Fig. 2.
Fig. 2.
Toca FC Concentrations The Toca FC serum concentrations (μg/mL) over time at increasing Toca FC doses (error bars are standard error). Cycles are approximately 1 week long and 4–8 weeks apart; measurements were normally on day 4 or 5 of the cycle.
Fig. 3.
Fig. 3.. Tumor mRNA expression profiles correlate with survival
Unsupervised hierarchical cluster of mRNA expression across sixty-four efficacy evaluable study tumor samples from twenty-six biopsies. The heatmap includes the 4313 mRNAs with the greatest variation in expression (Standard deviation > 0.8) with red bars representing increased and green bars decreased gene expression compared to normal human brain. Samples segregated into four main groups, which are color-coded in the dendrogram. Sample numbers subjects with glioblastoma that survived greater than 12 months after Toca 511 delivery are red, from subjects with glioblastoma that survived for less than 12 months are black, from subjects with grade III tumors are green, and other sample numbers are grey. Many of these 4313 mRNAs fell into one of five distinct clusters, characterized by common functional themes. Functional themes associated with the proteins encoded by mRNAs in specific clusters were identified using Reactome gene sets obtained from the Molecular Signatures Database. Examples of gene sets whose members are overrepresented in specific clusters are listed to the right of the heatmap along with associated p-values (hypergeometric distribution function).
Fig. 4.
Fig. 4.. Molecular classification of tumor samples from study subjects based on mRNA expression
(A) Bar plot representation of the number of glioblastoma samples in each molecular subtype: Classical (C) is black, Mesenchymal (M) is red, Neural (N) is green, Proneural (P) is blue. (B) Same as in (A), except for grade III samples. (C) Bar plot representation of molecular subtype for each subject, with the consensus subtype indicated by the color of subject identifier. Grey indicates no consensus was reached, i.e., the two samples profiled had different subtypes.
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