Fiedler, W., Giaccone, G., Lasch, P., van der Horst, I., Brega, N., Courtney, R., Abbattista, A., Shalinsky, D. R., Bokemeyer, C., and Boven, E.
Background: This phase I, open-label, dose-escalation study investigated SU14813, an oral multitargeted tyrosine kinase inhibitor, in adults with solid tumors.Patients and methods: Seventy-seven patients received once-daily SU14813, either for 4 weeks followed by 1 week off treatment (schedule 4/1) or continuously [continuous daily dosing (CDD)]. The primary end point was to determine the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed.Results: MTDs were 200 mg/day on schedule 4/1 and 100 mg/day with CDD. Adverse events included fatigue (64%), diarrhea (61%), nausea (44%), anorexia (43%), and vomiting (42%). SU14813 steady state was attained by day 8. Exposure increased in a generally dose-proportional manner and SU14813 was eliminated with a mean terminal half-life of 9–34 h. Target plasma concentrations (>100 ng/ml SU14813) were achieved and sustained over 12 h at ≥100 mg/day. Progression-free survival among the 1 complete responder and 12 partial responders was 1.4–53.2 months. Fifteen patients remained on treatment at 1 year and 3 patients at 2 years.Conclusion: SU14813 has manageable safety and tolerability and allows once-daily continuous oral dosing. SU14813 shows dose-proportional pharmacokinetics, with target plasma concentrations achieved at doses ≥100 mg/day. Clinically meaningful activity with durable responses was observed, meriting further study. [ABSTRACT FROM AUTHOR]