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

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

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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.

Original languageEnglish
Pages (from-to)1501-1510
Number of pages10
JournalInvestigational New Drugs
Issue number4
Publication statusPublished - 2012 Aug 1


All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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