title: 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).
authors.affiliation: Department of Neuro-Oncology and Department of Neurosurgery, 710 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: New Jersey Neuroscience Institute, John F. Kennedy Medical Center, 65 James Street, Edison, NJ 08820, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Landolfi
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hogan
authors.affiliation: New Jersey Neuroscience Institute, John F. Kennedy Medical Center, 65 James Street, Edison, NJ 08820, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bloomfield
authors.affiliation: Moores Cancer Center, Department of Neurosciences, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Bob
authors.initials: B
authors.lastname: Carter
authors.affiliation: Moores Cancer Center, Department of Neurosciences, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Ohio State University Wexner Medical Center, 410 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Elder
authors.affiliation: Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Kalkanis
authors.affiliation: Moores Cancer Center, Department of Neurosciences, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.affiliation: Department of Neuro-Oncology and Department of Neurosurgery, 710 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
authors.forename: Ian Y
authors.initials: IY
authors.lastname: Lee
authors.affiliation: Department of Neuro-Oncology and Department of Neurosurgery, 710 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Department of Neuro-Oncology and Department of Neurosurgery, 710 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Phioanh Leia
authors.initials: PL
authors.lastname: Nghiemphu
authors.affiliation: Moores Cancer Center, Department of Neurosciences, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Piccioni
authors.affiliation: Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Walbert
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chu
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Das
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Diago
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Gammon
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gruber
authors.affiliation: Ribomed Biotechnologies Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA. University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.affiliation: Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
authors.affiliation: Ribomed Biotechnologies Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: David
authors.initials: D
authors.lastname: McCarthy
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Ostertag
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Robbins
authors.affiliation: Tocagen Inc., 3030 Bunker Hill Street, San Diego, CA 92109, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Aguirre
authors.affiliation: Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. vogelbm@ccf.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
mesh_terms: D016001:Confidence Intervals; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005437:Flucytosine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D012190:Retroviridae / Q000235:genetics*
chemical_list: D011355:Prodrugs; D012333:RNA, Messenger; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil