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Cancer Therapy: Clinical

Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors

Andrew J. Brenner, Yael C. Cohen, Eyal Breitbart, Livnat Bangio, John Sarantopoulos, Francis J. Giles, Ernest C. Borden, Dror Harats and Pierre L. Triozzi
Andrew J. Brenner
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Yael C. Cohen
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Eyal Breitbart
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Livnat Bangio
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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John Sarantopoulos
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Francis J. Giles
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Ernest C. Borden
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Dror Harats
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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Pierre L. Triozzi
Authors' Affiliations: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas; VBL Therapeutics, Or Yehuda, Israel; HRB Clinical Research Facilities, National University of Ireland Galway & Trinity College Dublin, Ireland; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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DOI: 10.1158/1078-0432.CCR-12-2079 Published July 2013
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  • Figure 1.
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    Figure 1.

    Mechanism of action of VB-111. VB-111 targeted to angiogenic endothelial cells.

  • Figure 2.
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    Figure 2.

    A, pharmacokinetics: copies of Ad-5 DNA detected in whole blood (mean) by treatment cohort. Dose response shows at least 2-log reduction in Ad-5 levels by RT-PCR at day 56. B, levels of anti-Ad-5 IgG postdosing, cohorts 6–7. Levels reach a plateau at 14 to 28 days, without apparent dose response.

  • Figure 3.
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    Figure 3.

    Tumor response, overall survival, and progression-free survival. A, cohorts 1–5 tumor response at day 56. B, cohorts 6 and 7 tumor response at day 56. C, overall survival: 187 versus 173 days versus not reached in cohort 1–5 versus 6 versus 7, respectively (P = 0.012). (Continued on the following page). D, time to progressive disease: 31 versus 55 versus 121 days in cohort 1–5 versus 6 versus 7, respectively (P = 0.24). E, overall survival in cohort 1–6 versus 7: 173 days versus not reached (P = 0.0098). F, time to progressive disease in cohort 1–6 versus 7: 34.5 vs. 121 days (P = 0.10).

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    Figure 4.

    Partial response (RECIST criteria) in a patient with metastatic papillary thyroid cancer, radioiodine resistant. At 6 months, there is a 30% reduction in the lesion diameter, central necrosis, and no pressure on trachea.

Tables

  • Figures
  • Table 1.

    Demographics and baseline characteristics

    N = 33
    Age, median (range), y59 (35—77)
    Gender
     Male17 (52%)
     Female16 (48%)
    Karnofsky, median (range)90 (70–100)
    Tumor type
     Colorectal/adenocarcinoma11
     Carcinoid/neuroendocrine4
     NSCLC3
     RCC3
     Melanoma2
     Sarcoma2
     Thyroid2
     Merkel cell1
     Small cell lung1
     Bladder/transitional cell1
     Gastrointestinal stromal tumor1
     Testicular/sex cord1
     Esophageal adenocarcinoma1
    Treatment history
     Surgery24 (73%)
     Radiotherapy15 (45%)
     Chemotherapy29 (88%)
     1 prior regimen2 (6%)
     2 prior regimens9 (6%)
     ≥3 prior regimens18 (55%)

    Abbreviations: NSCLC, non–small cell lung cancer; RCC, renal cell carcinoma.

    • Table 2.

      Summary of adverse events

      Cohorts 1–4 (n = 12)Cohort 5 (n = 3)Cohort 6 (n = 12)Cohort 7 (n = 6)Total (N = 33)
      Adverse eventGrade 1–2Grade 3Grade 1–2Grade 3Grade 1–2Grade 3Grade 1–2Grade 3Grade 1–2Grade 3
      Frequent drug-related adverse events
        Nausea0000202040
        Chills0010602090
        Fever10209051181
        aPTT prolonged0000300030
        ALT increased0000003030
        AST increased0000103040
        Anorexia0010200030
        Dizziness0010002030
        Hyperhidrosis0000300030
      Cohorts 1–4 (n = 12)Cohort 5 (n = 3)Cohort 6 (n = 12)Cohort 7 (n = 6)Total (n = 33)
      AllRelatedAllRelatedAllRelatedAllRelatedAllRelated
      All grade 3–4 adverse events
        Abdominal pain/cramping0000101020
        Asthenia0000100010
        Disease progression1000000010
        Fatigue2000000020
        Pyrexia0000001111
        LFT increase0000100010
        Hyperbilirubinemia0000100010
        Anemia1000000010
        Hemoglobin decreased1000000010
        Hyperglycemia0000100000
        Electrolyte disorders5000100060
        Spinal cord compression0000001010
        Suicidal ideation0000100010

      NOTE: All events occurring in 3 or more patients and all grade 3–4 events.

      Abbreviation: LFT, liver function test.

      • Table 3.

        Patient disease response

        Individual patient dataCohort summary
        Day 28Day 56PFSOS
        CohortPatientCancer typeDay 28Day 56SDPDPRSDPDPR(median), mo(median), mo
        101–001Gastrointestinal stromal tumorPDPD1/3 (33%)2/3 (67%)0/3 (0%)0/3 (0%)2/3 (67%)0/3 (0%)1.03.9
        01–002SarcomaSDLTFU
        01–003Testicular/sex cord carcinomaPDPD
        201–004TCC bladderPDPD1/3 (33%)2/3 (67%)0/3 (0%)0/3 (0%)3/3 (100%)0/3 (0%)0.910.5
        01–005SarcomaSDPD
        01–006CRCPDPD
        301–007CRCSDSD1/3 (33%)2/3 (67%)0/3 (0%)1/3 (33%)2/3 (66%)0/3 (0%)1.98.5
        01–008MelanomaPDPD
        01–009NSCLCPDPD
        401–010CRCSDSD1/3 (33%)1/3 (33%)0/3 (0%)1/3 (33%)1/3 (33%)0/3 (0%)0.93.7
        02–013CRCPDPD
        01–014NSCLCLTFULTFU
        502–020CRCPDPD1/3 (33%)2/3 (67%)0/3 (0%)1/3 (33%)2/3 (67%)0/3 (0%)0.92.7
        02–021SCLCSDSD
        01–024CRCPDPD
        602–022CarcinoidSDSD8/12 (67%)4/12 (33%)0/12 (0%)5/12 (42%)6/12 (50%)0/12 (0%)1.85.8
        02–025MelanomaSDN/A
        02–026Papillary thyroid carcinomaSDSD
        02–027CRCPDPD
        02–028CRCSDSD
        01–029NETSDSD
        02–030CRCSDSD
        02–032RCCSDPD
        01–033CRCPDPD
        02–035Merkel cell carcinomaSDPD
        01–036Esophageal carcinomaPDPD
        01–038CRCPDPD
        701–039NETPDPD4/6 (67%)2/6 (33%)0/6 (0%)4/6 (67%)2/6 (33%)0/6 (0%)4.016.2
        02–040Medullary thyroid carcinomaSDSD
        01–041NETSDSD
        01–042NSCLCSDSD
        02–043RCCSDSD
        02–044RCCPDPD

        Abbreviations: CRC, colorectal carcinoma; LTFU, lost to follow-up; NET, neuroendocrine tumor; NSCLC, non–small cell carcinoma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma; SCLC, small cell lung carcinoma; SD, stable disease; TCC, transitional cell carcinoma.

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        Clinical Cancer Research: 19 (14)
        July 2013
        Volume 19, Issue 14
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        Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors
        Andrew J. Brenner, Yael C. Cohen, Eyal Breitbart, Livnat Bangio, John Sarantopoulos, Francis J. Giles, Ernest C. Borden, Dror Harats and Pierre L. Triozzi
        Clin Cancer Res July 15 2013 (19) (14) 3996-4007; DOI: 10.1158/1078-0432.CCR-12-2079

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        Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors
        Andrew J. Brenner, Yael C. Cohen, Eyal Breitbart, Livnat Bangio, John Sarantopoulos, Francis J. Giles, Ernest C. Borden, Dror Harats and Pierre L. Triozzi
        Clin Cancer Res July 15 2013 (19) (14) 3996-4007; DOI: 10.1158/1078-0432.CCR-12-2079
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