Phase I/II and Pharmacodynamic Study of Dovitinib (TKI258), an Inhibitor of Fibroblast Growth Factor Receptors and VEGF Receptors, in Patients with Advanced Melanoma

Abstract

Purpose: Dovitinib (TKI258) is an orally available inhibitor of fibroblast growth factor (FGF), VEGF, and platelet-derived growth factor receptors. This phase I/II dose-escalation study was conducted to evaluate the safety, pharmacodynamics, and preliminary efficacy of dovitinib in the treatment of advanced melanoma.Experimental Design: Patients with advanced melanoma resistant or refractory to standard therapies or for whom no standard therapy was available were enrolled. Dovitinib was administered at doses ranging from 200 to 500 mg/d.Results: Forty-seven patients were enrolled. The most frequently reported adverse events were fatigue (77%; grade !3, 28%), diarrhea (77%; grade !3, 11%), and nausea (77%; grade !3, 9%). Six dose-limiting toxicities were observed in the 400-mg and 500-mg dose cohorts, which consisted of grade 3 nausea, fatigue, and diarrhea and grade 4 fatigue events. The maximum tolerated dose was 400 mg/d. The best tumor response was stable disease, which was observed in 12 patients. Increases in plasma FGF23, VEGF, and placental growth factor and decreases in soluble VEGF receptor 2 were noted during the first cycle of treatment, consistent with FGF receptor (FGFR) and VEGF receptor (VEGFR) inhibition. Dynamic contrastenhanced MRI analysis showed a dose-dependent decrease in tumor blood flow and vascular permeability with dovitinib therapy. A decrease in FGFR phosphorylation was observed in paired tumor biopsy samples from a patient treated with dovitinib at a dose of 400 mg/d.Conclusions: At a dose of 400 mg/d, dovitinib showed an acceptable safety profile and limited clinical benefit and inhibited FGFR and VEGFR. Clin Cancer Res; 17(23); 7451-61. Ó2011 AACR.

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…An increase in plasma FGF23, VEGF, and placental growth factor levels and a decrease in soluble VEGFR2 were observed during the fi rst cycle of treatment. As the modulation of plasma FGF23 has been shown to act as a surrogate pharmacodynamic biomarker of FGFR1 inhibition, the results of the pharmacodynamic studies were consistent with FGFR and VEGFR inhibition ( 77 ).…”

Phase II Results of Dovitinib (TKI258) in Patients with Metastatic Renal Cell Cancer

“…Collection of plasma samples for pharmacodynamic analyses was described previously (15,18). Briefly, plasma samples were assessed by ELISA for FGF23 (Kainos Laboratories, Inc.) and a panel of markers associated with angiogenesis, including basic FGF (bFGF), placental growth factor (PIGF), soluble VEGFR1/2 (sVEGFR1/2), and VEGF (Meso Scale Discovery).…”

“…3). A statistically significant increase from baseline in FGF23, a surrogate pharmacodynamic biomarker for FGFR1 inhibition (18), was observed in patient plasma samples following treatment with dovitinib at cycle 1, day 15 (124% increase; 95% CI, 74%-189%; P < 0.0001) and cycle 1, day 26 (47% increase; 95% CI, 13%-90%; P ¼ 0.0063). Levels of the angiogenesis biomarkers were increased (PIGF, VEGF) or decreased (sVEGFR1, sVEGFR2) following treatment, consistent with the antiangiogenic effect associated with dovitinib-induced inhibition of VEGFR.…”

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

“…We also examined the effect of E7090 on plasma FGF23 level. FGF23 belongs to a subgroup of FGF ligands that function as endocrine factors, and elevation of plasma FGF23 has been demonstrated to be a surrogate pharmacodynamic biomarker of FGFR inhibition in both nonclinical and clinical studies (27,28). Dose-dependent elevation of plasma FGF23 was observed at 24 hours after drug administration (Fig.…”