Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies

Purpose: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food. Patients and Methods: Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m(2) thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m(2) thrice daily. Pharmacokinetics was done on days 1, 28, and 56. Results: Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m(2) thrice daily experienced no DLT. At dose level 200 mg/m(2) thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and C-max (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples. Conclusions:The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m(2). Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.