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

Bart C. Kuenen, Giuseppe Giaccone, Rita Ruijter, Astrid Kok, Casper Schalkwijk, Klaas Hoekman, Herbert M. Pinedo

Research output: Contribution to journalArticle

Abstract

Purpose: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-β, 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/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 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/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 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 interteukin-6, was observed in serial blood samples. Conclusions: The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.

Original languageEnglish (US)
Pages (from-to)6240-6246
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number17
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Kuenen, B. C., Giaccone, G., Ruijter, R., Kok, A., Schalkwijk, C., Hoekman, K., & Pinedo, H. M. (2005). Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies. Clinical Cancer Research, 11(17), 6240-6246. https://doi.org/10.1158/1078-0432.CCR-04-2466