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.