Research ArticleCancer

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

See allHide authors and affiliations

Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ra75
DOI: 10.1126/scitranslmed.aad9784
  • Fig. 1. OS and comparison of Toca 511 and Toca FC to lomustine.

    (A) The OS Kaplan-Meier plot of subjects who have received higher [cohorts 4 to 7a (C4–7a)] versus lower doses [cohorts 1 to 3 (C1–3)] of Toca 511 and Toca FC. NR, not reached. (B) The OS Kaplan-Meier plot of subjects with glioblastoma at first or second recurrence who received Toca 511 and Toca FC versus the lomustine external control. (C) The OS Kaplan-Meier plot from initial diagnosis of subjects with glioblastoma at first or second recurrence treated with Toca 511 and Toca FC versus lomustine external control. Tg 511-11-01 and Tg 11-01 are abbreviations for Toca 511 + Toca FC treatment.

  • Fig. 2. Toca FC concentrations.

    The Toca FC serum concentrations (microgram/milliliter) over time at increasing Toca FC doses (means ± SE). Cycles are about 1 week long and 4 to 8 weeks apart; measurements were normally on day 4 or 5 of the cycle.

  • Fig. 3. Tumor mRNA expression profiles and correlation with survival.

    Unsupervised hierarchical cluster of mRNA expression across 64 efficacy evaluable study tumor samples from 26 biopsies. The heatmap includes the 4313 mRNAs with the greatest variation in expression (SD, >0.8), with red and green bars representing increased and decreased gene expression, respectively, compared to normal human brain. Samples were segregated into four main groups, which are color-coded in the dendrogram. Sample numbers are red, black, green, and gray from subjects with glioblastoma who survived more than 12 months after Toca 511 delivery, from subjects with glioblastoma that survived less than 12 months, from subjects with grade 3 tumors, and from other sample numbers, respectively. 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; P values are represented in figure parentheses). ECM, extracellular matrix.

  • Fig. 4. Molecular classification of tumor samples from study subjects based on mRNA expression.

    (A) Bar plot representation of the number of glioblastoma (grade 4) samples in each molecular subtype: classical (C) (black), mesenchymal (M) (red), neural (N) (green), and proneural (P) (blue). (B) Same as in (A), except for grade 3 samples. (C) Bar plot representation of molecular subtype for each subject, with the predominant subtype indicated by the color of the subject identifier. Gray indicates that no consensus was reached, which means that the two samples profiled had different subtypes.

  • Table 1. Toca 511 and Toca FC OS. K-M, Kaplan-Meier.
    PopulationnMedian survival, 95% CI (months)
    Efficacy evaluable—HGG4313.6 (10.8–20.0)
    Efficacy evaluable—HGG, first and second recurrence3214.4 (11.3–32.3)
    Glioblastoma efficacy evaluable3511.6 (9.2–14.6)
    Glioblastoma efficacy evaluable—first and second recurrence2713.6 (11.1–20.0)
    Landmark OS for efficacy evaluable—HGG43K-M survival rate
    OS687.9%
    OS972.4%
    OS1252.5%
    OS2431.6%
  • Table 2. Demographics of glioblastoma at first or second recurrence: Toca 511 and Toca FC versus lomustine.
    Treatment group
    characteristics
    Toca 511 and Toca FC
    (n = 27)
    n (%)
    Lomustine
    (n = 84)
    n (%)
    Sex
      Female4 (14.8)33 (39.3)
      Male23 (85.2)51 (60.7)
    Age, years
      Median6154
      Range41–7118–75
    Age, years
      <505 (18.5)27 (32.1)
      ≥5022 (81.5)57 (67.9)
    KPS
      70–807 (25.9)41 (48.8)
      90–10020 (74.1)43 (51.2)
    Time from diagnosis (months)
      Median11.611.5
      Range5.1–49.44.4–92.1
    Recurrence
      First19 (70.4)65 (77.4)
      Second8 (29.6)19 (22.6)
    Baseline steroid administration
      Yes23 (85.2)46 (54.8)
      No4 (14.8)38 (45.2)
  • Table 3. Landmark OS in glioblastoma at first or second recurrence with Toca 511 and Toca FC versus lomustine.
    Treatment groupToca 511 and Toca FC
    (n = 27)
    Lomustine
    (n = 84)
    P value
    Landmark OS rate
    OS696.0%61.8%<0.001
    OS983.5%38.4%<0.001
    OS1254.8%26.4%0.017
    OS2429.1%9.1%0.065
  • Table 4. Summary of adverse and serious adverse events.
    All gradesGrade ≥3
    Toca 511 and Toca FC
    n = 27 n (%)
    Lomustine
    n = 84 n (%)
    Toca 511 and Toca FC
    n = 27 n (%)
    Lomustine
    n = 84 n (%)
    Any treatment-emergent adverse event27 (100.0)70 (83.3)17 (63.0)45 (53.6)
    Related treatment-emergent adverse event11 (40.7)52 (61.9)1 (3.7)31 (36.9)
    Leading to study discontinuation treatment-emergent
    adverse event
    04 (4.8)04 (4.8)
    Treatment-emergent serious adverse event9 (33.3)24 (28.6)7 (25.9)21 (25.0)
    Related treatment-emergent serious adverse event2 (7.4)6 (7.1)1 (3.7)5 (6.0)

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/8/341/341ra75/DC1

    Materials and Methods

    Fig. S1. Simplified schematic for the phase 1 trial (NCT01470794).

    Fig. S2. Tumor-specific Toca 511 staining in re-resected tumors after multiple cycles of Toca FC.

    Fig. S3. Evidence of potential pseudoprogression on resected tumor after Toca 511 and Toca FC treatment.

    Fig. S4. Comparison of subjects with glioblastoma at first or second recurrence treated with Toca 511 and Toca FC to lomustine.

    Fig. S5. Peripheral blood CD4+ T cell modulation after Toca 511 and Toca FC dosing.

    Fig. S6. Tracking of Toca 511 DNA and RNA signal in whole blood and plasma over time.

    Fig. S7. Molecular classification of tumor samples from study subjects based on mRNA expression.

    Fig. S8. Intratumor versus intertumor heterogeneity in RNA expression profiles.

    Fig. S9. No relationship between variation in mRNA expression and confounding technical factors.

    Fig. S10. No correlation between neural subtype and prognosis in newly diagnosed glioblastoma.

    Fig. S11. Identification of an mRNA profile (SRNS) associated with longer survival after Toca 511.

    Fig. S12. No correlation between SRNS and prognosis in newly diagnosed glioblastoma.

    Fig. S13. Study survival–related neural subtype samples likely derive from nonenhancing regions of tumors.

    Fig. S14. Negative expression between SPOC1 expression and subject survival time with Toca 511 and Toca FC therapy.

    Fig. S15. MGMT promoter methylation.

    Table S1. Toca 511 and Toca FC: Baseline demographic and clinical characteristics.

    Table S2. Additional baseline demographic and clinical characteristics.

    Table S3. Dosing cohorts.

    Table S4. Detection of Toca 511 in re-resected tumors.

    Table S5. Best overall response in the efficacy evaluable population.

    Table S6. Adverse events and serious adverse events related to Toca 511 and Toca FC.

    Table S7. Related adverse events: Toca 511 and Toca FC compared to lomustine.

    Table S8. Adverse events regardless of attribution: Toca 511 and Toca FC compared to lomustine.

    Table S9. Summary of multivariate analysis for survival (TCGA neural signature).

    Table S10. Summary of multivariate analysis for survival (SRNS signature).

    Table S11. RNA sequencing normalized results (reads per kilobase of transcript per million mapped reads values).

    Table S12. SRNS gene list.

    Table S13. Subject summary.

    References (45, 46)

  • Supplementary Material for:

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

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

    *Corresponding author. Email: vogelbm{at}ccf.org

    Published 1 June 2016, Sci. Transl. Med. 8, 341ra75 (2016)
    DOI: 10.1126/scitranslmed.aad9784

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Simplified schematic for the phase 1 trial (NCT01470794).
    • Fig. S2. Tumor-specific Toca 511 staining in re-resected tumors after multiple cycles of Toca FC.
    • Fig. S3. Evidence of potential pseudoprogression on resected tumor after Toca 511 and Toca FC treatment.
    • Fig. S4. Comparison of subjects with glioblastoma at first or second recurrence treated with Toca 511 and Toca FC to lomustine.
    • Fig. S5. Peripheral blood CD4+ T cell modulation after Toca 511 and Toca FC dosing.
    • Fig. S6. Tracking of Toca 511 DNA and RNA signal in whole blood and plasma over time.
    • Fig. S7. Molecular classification of tumor samples from study subjects based on mRNA expression.
    • Fig. S8. Intratumor versus intertumor heterogeneity in RNA expression profiles.
    • Fig. S9. No relationship between variation in mRNA expression and confounding technical factors.
    • Fig. S10. No correlation between neural subtype and prognosis in newly diagnosed glioblastoma.
    • Fig. S11. Identification of an mRNA profile (SRNS) associated with longer survival after Toca 511.
    • Fig. S12. No correlation between SRNS and prognosis in newly diagnosed glioblastoma.
    • Fig. S13. Study survival–related neural subtype samples likely derive from nonenhancing regions of tumors.
    • Fig. S14. Negative expression between SPOC1 expression and subject survival time with Toca 511 and Toca FC therapy.
    • Fig. S15. MGMT promoter methylation.
    • Table S1. Toca 511 and Toca FC: Baseline demographic and clinical characteristics.
    • Table S2. Additional baseline demographic and clinical characteristics.
    • Table S3. Dosing cohorts.
    • Table S4. Detection of Toca 511 in re-resected tumors.
    • Table S5. Best overall response in the efficacy evaluable population.
    • Table S6. Adverse events and serious adverse events related to Toca 511 and Toca FC.
    • Table S7. Related adverse events: Toca 511 and Toca FC compared to lomustine.
    • Table S8. Adverse events regardless of attribution: Toca 511 and Toca FC compared to lomustine.
    • Table S9. Summary of multivariate analysis for survival (TCGA neural signature).
    • Table S10. Summary of multivariate analysis for survival (SRNS signature).
    • References (45, 46)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S11 (Microsoft Excel format). RNA sequencing normalized results (reads per kilobase of transcript per million mapped reads values).
    • Table S12 (Microsoft Excel format). SRNS gene list.
    • Table S13 (Microsoft Excel format). Subject summary.

Stay Connected to Science Translational Medicine

Navigate This Article