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A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer

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Summary

Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX. Methods This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS). Results A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 (p = 0.012). Conclusion TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.

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Clinical trials

This study is registered with JAPIC Clinical Trial Information, number JapicCTI-111403.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine,Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Jeeyun Lee

  2. Division of Hematology/Oncology, Department of Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Sang Joon Shin & Hyun Cheol Chung

  3. Division of Hematology/Oncology, Department of Medicine, Chonnam National University Hwasun Hospital, Gwangju, South Korea

    Ik Joo Chung

  4. Division of Hematology/Oncology, Department of Medicine, Asan Medical Center, Seoul, South Korea

    Tae Won Kim

  5. Division of Hematology/Oncology, Department of Medicine, Seoul St. Mary’s Hospital, Banpo, Seoul, South Korea

    Hoo-Geun Chun

  6. Division of Hematology/Oncology, Department of Medicine, Gachon University Gil Hospital, Incheon, South Korea

    Dong Bok Shin

  7. Division of Hematology/Oncology, Department of Medicine, Korea University Anam Hospital, Seoul, South Korea

    Yeul Hong Kim

  8. Division of Hematology/Oncology, Department of Medicine, Keimyung University Dongsan Hospital, Seoul, South Korea

    Hong Suk Song

  9. Division of Hematology/Oncology, Department of Medicine, Seoul National University Hospital, Seoul, South Korea

    Sae-Won Han

  10. Division of Hematology/Oncology, Department of Medicine, Kyungpook National University Hospital, Daegu, South Korea

    Jong Gwang Kim

  11. Division of Hematology/Oncology, Department of Medicine, National Cancer Center, Goyang-si, South Korea

    Sun Young Kim

  12. Division of Hematology/Oncology, Department of Medicine, Pusan National University Hospital, Pusan, South Korea

    Young Jin Choi

  13. Department of Medical Oncology, Severance Hospital, Yonsei University, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea

    Hyun Cheol Chung

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  1. Jeeyun Lee
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Correspondence to Hyun Cheol Chung.

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Lee, J., Shin, S.J., Chung, I.J. et al. A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer. Invest New Drugs 32, 561–568 (2014). https://doi.org/10.1007/s10637-014-0075-8

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