Phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664, a VEGFR/FGFR inhibitor in patients with advanced/metastatic solid tumors

Abstract

3051 Background: This is the first multiple-dose study with BMS-582664, an oral VEGFR/FGFR tyrosine kinase inhibitor (IC50 34, 10, 145, 125 nM for VEGFR2, VEGFR3, FGFR1 and FGFR2 respectively). Patients (pts) with metastatic solid tumors refractory to standard therapy were enrolled. Part A of this study has completed. Part B is ongoing to evaluate the effect of BMS-582664 on dynamic contrast enhanced MRI (DCE-MRI) parameters. Methods: Part A: Open label dose escalation, continuous qd schedule, 3 patients per cohort. The starting dose was 180 mg. Dose escalation continued until dose limiting toxicities (DLTs) at 1000 mg in 2/3 pts were observed. The next lower dose level (800 mg) was expanded to 6 pts. Blood sampling for pharmacodynamic [circulating endothelial cells (CECs) and Collagen IV ELISA] and PK analysis was performed on Days 1, 8 and 26. BMS-582664 (prodrug) and its active metabolite, BMS-540215 were analyzed using an LC/MS/MS assay. DCE-MRI was performed at 320 mg, 600 mg and 800 mg at baseline ×2, Days 2, 8 and 26. Results: Negligible BMS-582664 was detected. BMS-540215 AUC increased proportionally to dose increase across 180 mg to 1000 mg. The accumulation ratio (Day 26:Day 1) of C 24hr, C max and AUC was 4.8, 2.0 and 2.1 respectively at 1000 mg, but close to 1 at lower doses. The median time on study for all patients in Part A was 84 days. Conclusions: DLT was dizziness/fatigue. BMS-582664 has pharmacodynamic and anti-tumor activity and was well tolerated at ≤ 800 mg qd. [Table: see text][Table: see text]