Phase III trial of dovitinib (TKI258) versus sorafenib in patients with metastatic renal cell carcinoma after failure of anti-angiogenic (VEGF-targeted and mTOR inhibitor) therapies.

Abstract

TPS4683 Background: Standard first- and second-line treatments in metastatic renal cell carcinoma (mRCC) target the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. However, signaling through other pathways, including the fibroblast growth factor receptor (FGFR) pathway, may account for tumor resistance to these standard therapies. Dovitinib (TKI258) is an oral FGF, VEGF, and platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor, with IC50 values of ≈ 10 nM. In a phase II study of 59 RCC patients, many of whom had failed prior VEGF-targeted and mTOR inhibitor therapies, dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) was well tolerated and demonstrated promising anti-tumor effects, with progression-free survival (PFS) of 5.5 months (Angevin et al, ASCO 2011). Methods: Approximately 550 patients from over 26 countries will be randomized 1:1 in this multicenter, open-label, randomized phase III trial (NCT01223027) to receive dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) or sorafenib (400 mg twice daily). Eligible mRCC patients must have failed 1 VEGF-targeted therapy and 1 mTOR inhibitor (disease progression on or within 6 months of stopping the prior treatment). Patients will remain on study until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover is planned. The primary endpoint is PFS as determined by central radiology assessment according to RECIST v1.1, with evaluations performed every 8 weeks. Secondary endpoints include overall survival, overall response rate, safety, patient-reported outcomes, and pharmacokinetics. The pharmacodynamic effects of dovitinib on plasma/serum biomarkers will also be explored. The data monitoring committee last reviewed the trial on 20 December 2011 and recommended that the trial continue as planned. This is the first third-line randomized clinical trial in mRCC to evaluate a multitargeted inhibitor of FGFR.