First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors.

Abstract

3040 Background: Sulfatinib is a highly selective oral small molecule tyrosine dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: This phase I dose-escalation study were to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity, and to assess potential pharmacodynamics (PD) markers of sulfantinib when given orally in continuous cycles of 28 days, until disease progression or unacceptable toxicity. Results: Forty one patients (pts) have been enrolled and treated with doses of 50-300mg once or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and 93% gastrointestinal tumors. Common adverse events (AEs) included fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3 coagulation disorders, upper gastrointestinal bleeding and impaired liver function were observed in the 50 and 265mg qd and 150mg bid cohorts, respectively. MTD has not been reached and the dose escalation is ongoing. Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or longer, including liver and neuroendocrine cancer, GIST and solid-pseudopapillary tumor of pancreas. A patient with GIST had SD of 9 months at 265mg qd. There was a significant decrease in soluble VEGFR2 level and increase in FGF23 level after 4-week treatment comparing to the baseline at 265 mg or higher daily doses, indicating inhibition of both VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and AUC displayed dose-proportional increases and no obvious accumulation occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to 300 mg per day and demonstrated preliminary anti-tumor activity, especially in liver cancer and GIST. PD marker analysis indicates dual inhibition of VEGFR and FGFR. PK data suggests good dose proportionality in exposure without marked drug accumulation.