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A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy

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Summary

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m2 b.i.d. on Days 1–14 and oxaliplatin 130 mg/m2 i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. Cmax and AUC0-t of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased Cmax and AUC0-t less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.

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Authors and Affiliations

  1. Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, 250 Seongsanno, Seodaemun-gu, 120–752, Seoul, South Korea

    Sang Joon Shin, Minkyu Jung, Hei-Cheul Jeung, Hye Ryun Kim, Sun Young Rha, Jae Kyung Roh, Hyun Cheol Chung & Joong Bae Ahn

  2. Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, 250 Seongsanno, Seodaemun-gu, 120–752, Seoul, South Korea

    Sang Joon Shin, Hei-Cheul Jeung, Sun Young Rha, Jae Kyung Roh, Hyun Cheol Chung & Joong Bae Ahn

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  1. Sang Joon Shin
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  2. Minkyu Jung
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  3. Hei-Cheul Jeung
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Correspondence to Joong Bae Ahn.

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Shin, S.J., Jung, M., Jeung, HC. et al. A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy. Invest New Drugs 30, 1501–1510 (2012). https://doi.org/10.1007/s10637-011-9683-8

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  • DOI: https://doi.org/10.1007/s10637-011-9683-8

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