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Molecular Cancer Therapeutics
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Molecular Medicine in Practice

Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Isamu Okamoto, Hiroyasu Kaneda, Taroh Satoh, Wataru Okamoto, Masaki Miyazaki, Ryotaro Morinaga, Shinya Ueda, Masaaki Terashima, Asuka Tsuya, Akiko Sarashina, Koichi Konishi, Tokuzo Arao, Kazuto Nishio, Rolf Kaiser and Kazuhiko Nakagawa
Isamu Okamoto
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Hiroyasu Kaneda
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Taroh Satoh
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Wataru Okamoto
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Masaki Miyazaki
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Ryotaro Morinaga
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Shinya Ueda
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Masaaki Terashima
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Asuka Tsuya
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Akiko Sarashina
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Koichi Konishi
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Tokuzo Arao
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Kazuto Nishio
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Rolf Kaiser
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Kazuhiko Nakagawa
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DOI: 10.1158/1535-7163.MCT-10-0379 Published October 2010
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  • Figure 1.
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    Figure 1.

    Structure of BIBF 1120.

  • Figure 2.
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    Figure 2.

    Mean (± SD) plasma concentration–time profiles of BIBF 1120 after single (A; day 1) and multiple (B; day 29) administration of 150, 200, and 250 mg BIBF 1120 twice daily.

  • Figure 3.
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    Figure 3.

    sVEGFR2 levels in plasma after BIBF 1120 treatment. A, plasma sVEGFR2 levels decreased during the 4-week treatment period. B, the decrease in sVEGFR2 at cycle 1, day 29 showed a modest inverse correlation with trough plasma drug levels of BIBF 1120 (r = −0.46).

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    Figure 4.

    Levels of circulating CD117-BMD progenitor cells after BIBF 1120 treatment. A, representative flow cytometric analysis for determining the number of CD117-positive–BMD progenitor cells defined as CD45dimCD34+CD117+. B, circulating levels of CD45dimCD34+CD117+ cells decreased during the 4-week treatment period.

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  • Table 1.

    Patient characteristics

    CharacteristicNo. of patients
    Median (range) age (y)62 (41-81)
    Sex
        Male11 (52%)
        Female10 (48%)
    Performance status (ECOG)
        05 (24%)
        116 (76%)
    Previous therapy
        Surgery18 (86%)
        Chemotherapy19 (91%)
        Radiotherapy6 (29%)
    Tumor types
        Colorectal cancer14 (67%)
        Non–small cell lung cancer1 (4.8%)
        Small cell lung cancer1 (4.8%)
        Esophagus sarcoma1 (4.8%)
        Adrenal carcinoma1 (4.8%)
        Renal cell carcinoma1 (4.8%)
        Adenoid cystic carcinoma1 (4.8%)
        Unknown primary site1 (4.8%)

    Abbreviation: ECOG, Eastern Cooperative Oncology Group.

    • Table 2.

      Dose-escalation scheme and DLT

      BIBF 1120 dose (mg bid)No. of patientsDLTs
      TotalDLT in first course
      15030
      200123ALT and γ-GT increase; ALT increase; AST, ALT, and γ-GT increase
      25063AST and ALT increase; ALT increase; γ-GT increase

      Abbreviations: bid, twice daily; γ-GT, γ–glutamyl transferase.

      • Table 3.

        Adverse events (≥10% incidence) related to BIBF 1120 in all treatment courses

        BIBF 1120 dose150 bid (N = 3)200 bid (N = 12)250 bid (N = 6)Total (N = 21)
        CTCAE grade1/23/41/23/41/23/4All
        NNNNNNN(%)
        ALT increased0044321361.9
        AST increased0062311257.1
        γ-GT increased0044221257.1
        Vomiting1090201257.1
        Anorexia1080201152.4
        Fatigue2060211152.4
        ALP increased005130942.9
        Nausea105020838.1
        Diarrhea005020733.3
        Hemoptysis103000419.0
        Upper abdominal pain101020419.0
        Weight decreased004000419.0
        Abdominal pain102000314.3
        Hypertension111000314.3
        Rash002010314.3
        Proteinuria102000314.3
        LDH increased002010314.3

        NOTE: Presented is the highest ever reached CTCAE grade. One patient may have experienced >1 event.

        Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; bid, twice daily; γ-GT, γ–glutamyl transferase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase.

        • Table 4.

          Pharmacokinetic variables of BIBF 1120 after a single dose (day 1) and multiple dosing for 29 days

          Single doseBIBF 1120 dose (mg)
          150 (N = 3)200 (N = 12)250 (N = 6)
          Cmax, ng/mL28.9 (61.5)52.0 (64.3)99.8 (70.3)
          tmax*, h2.00 (1.00-6.00)2.98 (1.98-4.00)2.98 (1.00-4.07)
          t1/2, h10.3 (15.8)10.2 (30.4)9.53 (10.8)†
          AUC0-12, ng·h/mL145 (88.3)233 (40.9)399 (64.9)
          Multiple dosing150 (N = 3)200 (N = 7)250 (N = 3)
          Cmax,ss, ng/mL38.8 (107)67.6 (74.3)62.9 (14.4)
          tmax,ss, h2.00 (1.98-4.00)2.97 (1.98-3.98)2.00 (1.00-4.00)
          t1/2,ss, h20.4 (55.3)19.9 (75.5)‡23.8 (39.4)§
          AUCss, ng·h/mL207 (135)423 (66.2)411 (9.15)
          Rac1.42 (35.4)1.70 (40.9)1.50 (79.0)

          NOTE: Geometric mean (geometric coefficient of variation %).

          Abbreviations: tmax,ss, time to reach maximum plasma concentrations at steady state; AUC, area under the curve.

          • ↵*Median (range).

          • ↵†N = 5.

          • ↵‡N = 6.

          • ↵§N = 2.

        Additional Files

        • Figures
        • Tables
        • Supplementary Data, Okamoto, et al.

          Files in this Data Supplement:

          • Supplementary Figure 1
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        Molecular Cancer Therapeutics: 9 (10)
        October 2010
        Volume 9, Issue 10
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        Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
        Isamu Okamoto, Hiroyasu Kaneda, Taroh Satoh, Wataru Okamoto, Masaki Miyazaki, Ryotaro Morinaga, Shinya Ueda, Masaaki Terashima, Asuka Tsuya, Akiko Sarashina, Koichi Konishi, Tokuzo Arao, Kazuto Nishio, Rolf Kaiser and Kazuhiko Nakagawa
        Mol Cancer Ther October 1 2010 (9) (10) 2825-2833; DOI: 10.1158/1535-7163.MCT-10-0379

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        Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
        Isamu Okamoto, Hiroyasu Kaneda, Taroh Satoh, Wataru Okamoto, Masaki Miyazaki, Ryotaro Morinaga, Shinya Ueda, Masaaki Terashima, Asuka Tsuya, Akiko Sarashina, Koichi Konishi, Tokuzo Arao, Kazuto Nishio, Rolf Kaiser and Kazuhiko Nakagawa
        Mol Cancer Ther October 1 2010 (9) (10) 2825-2833; DOI: 10.1158/1535-7163.MCT-10-0379
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