Dovitinib (formerly TKI258)

Dovitinib (formerly TKI258) is a multi-target tyrosine kinase inhibitor under development by Novartis (earlier acquired from Chiron).  Targets of this drug include:

  • VEGF receptors 1, 2, and 3
  • PDGF receptor beta
  • fibroblast growth factor receptors 1, 2, and 3
  • fetal liver TK receptor 3
  • KIT
  • Ret
  • TrkA
  • CSF-1

Definition from NCI Drug Dictionary:  The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types.

Clinical trials relevant to GIST

Efficacy and Safety of Dovitinib in Patients With Gastrointestinal Stromal Tumors Refractory and/or Intolerant to Imatinib (MACS1755)

Dovitinib for Imatinib/Sunitinib-failed Gastrointestinal Stromal Tumors (GIST)

Published information about dovitinib

A Phase I clinical trial using TKI258 in 35 patients with solid tumors has been published:

Sarker D, Molife R, Evans TR, Hardie M, Marriott C, Butzberger-Zimmerli P, Morrison R, Fox JA, Heise C, Louie S, Aziz N, Garzon F, Michelson G, Judson IR, Jadayel D, Braendle E, de Bono JS.
A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.
Clin Cancer Res. 2008 Apr 1;14(7):2075-81.  PMID: 18381947

One GIST patient in this study (who had previously experienced progression on imatinib and on sorafenib) showed stable disease for 8 months at a dose of 75 mg/day on an intermittent schedule.