A phase I study of BAY 43–9006, a dual inhibitor of Raf and VEGFR kinases, in Japanese patients with solid cancers

Abstract

3062 Background BAY 43–9006 is a novel inhibitor of Raf kinase and vascular endothelial growth factor (VEGF) tyrosine kinases. BAY 43–9006 has shown in vivo antitumor activity against various cancers by inhibiting tumor cell proliferation and angiogenesis. We have conducted a phase I study of BAY 43–9006 in Japanese cancer patients to decide a recommended dose and to clarify profiles of toxicities and pharmacokinetics. Methods Patients with solid tumors refractory to standard therapy, adequate organ functions, performance status of 0 or 1, and a life expectancy of ≥ 12 weeks were enrolled. Successive cohorts of patients received a single oral dose of 100 to 600 mg followed by a 7-day observation period and then received the same dose bid without interruption. Results Thirty-one patients including 10 non-small cell lung (NSCLC) and 3 renal cell cancer patients were treated. Three, 15, 6 and 7 patients were treated at 100, 200, 400 and 600 mg bid, respectively. Common drug-related adverse events were skin toxicities, laboratory data abnormalities, diarrhea and anorexia. At 200 mg bid, one patient developed grade 3 diarrhea and another two had grade 4 transient elevations of pancreatic enzymes. Grade 3/4 asymptomatic and transient elevations of pancreatic enzymes were observed in 2/3 patients at 400 and 600 mg bid, respectively. DLT definition was modified to consider not only NCI-CTC grading but also clinical significance. At 600 mg bid, dose-limiting grade 3 fatigue was observed in one patient and 5 patients experienced grade 2 hand-foot syndrome that were more painful and severe than those at 400 mg bid. The AUC and Cmax of BAY 43–9006 linearly increased with dose. At 400 mg bid, plasma trough concentrations (1.22 - 14.77 mg/L) exceeded the IC50 (1.2 mg/L) of BAY 43–9006 shown to inhibit tumor cell proliferation. Partial responses by RECIST were observed in a NSCLC patient (200 mg bid) and a renal cell cancer patient (600 mg bid). Two other NSCLC patients treated at 200 or 400 mg bid had stable disease ≥ 24 weeks. Conclusions BAY 43–9006 at 400 mg bid is recommended for phase II studies based on safety and efficacy data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Yakuhin, Ltd. Bayer Yakuhin, Ltd.