Phase I, pharmacokinetic, and biological studies of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, administered after meals with solid tumors

PURPOSE: TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factors receptor 1. In this study, we assessed the recommended dose with TSU-68 administration of twice-daily (b.i.d.) or thrice-daily (t.i.d.) after meals for 4 weeks in Japanese patients with solid tumors based on the safety and tolerability and investigated the relationship between angiogenesis biomarker and clinical outcomes. METHODS: The study design was a dose-escalation method with alternating enrollment of b.i.d. administration and t.i.d. administration after meal by traditional three-patient cohort. RESULTS: We enrolled 24 patients at doses of 200, 400, and 500 mg/m(2) b.i.d. or 200 and 400 mg/m(2) t.i.d. No dose-limiting toxicity (DLT) occurred in the 200 mg/m(2) b.i.d. or t.i.d., and 3 patients experienced DLTs at 400 mg/m(2) b.i.d. or 400 mg/m(2) t.i.d. As main toxicity, blood albumin decreased, malaise, diarrhea, alkaline phosphatase increased, anorexia, abdominal pain, nausea, and vomiting were observed as almost all grade 1–2. There were no apparent differences in pharmacokinetic parameters between days 2 and 28 after the repeated b.i.d. and t.i.d. doses. Although tumor shrinkage was not observed, the disease control rate was 41.7%. As an angiogenesis-related factor of stratified analysis, plasma vascular endothelial growth factor and plasminogen activator inhibitor-1 were detected as a significant increase with progressive disease patients. CONCLUSIONS: A recommended dosage of TSU-68 for this administration schedules was estimated to be 400 mg/m(2) or less b.i.d.