Dovitinib for Imatinib/Sumitinib-failed Gastrointestinal Stromal Tumors (GIST): TKI258
Status:
Completed
Trial end date:
2013-03-01
Target enrollment:
Participant gender:
Summary
With discovery of KIT mutations and the advent of KIT tyrosine kinase inhibitor imatinib
(GlivecTM, Novartis), there has been substantial improvement in overall survival in patients
with advanced and/or metastatic gastrointestinal tumors (GIST). Recently, sunitinib
(SuteneTM, Pfizer) showed activity as second-line therapy in GIST patients after failure with
imatinib. However, virtually all patients will eventually progress or become intolerable
after the first-line imatinib and the second-line sunitinib. Dovitinib (TKI258, Novartis) is
a multi-kinase inhibitor. TKI258 is a potent inhibitor of the VEGFR 1, 2, and 3, FGFR1, 2 and
3, PDGFRβ, Kit, RET, TrkA, CSF 1R, and FLT3 with inhibitory concentration 50% (IC50s) of less
than 40nM. Stem cell factor (SCF) also termed KIT ligand, or steel factor has been shown to
modulate tumor angiogenesis. In cultured human endothelial cells and Kit expressing cancer
cells, TKI258 inhibits VEGF- and SCF-stimulated mitogenesis. .