Phase I trial of SU014813 in patients (pts) with advanced solid malignancies

Abstract

3521 Background: SU014813 is an oral multi-targeted small molecule RTK inhibitor of VEGFRs, PDGFRs, sKIT & FLT-3 at nM concentrations. This study was designed to determine the safety, PK, PD, & preliminary efficacy of SU014813. Methods: Cohorts of pts with (w/) relapsed or refractory solid tumors received oral SU014813 at 25, 50, 100, 150, 200, or 250 mg on a 4 wks on/1 wk off (4/1), or 100 or 150 mg on a continuous dose (CD) schedule. The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered DLT during Cycle 1. Primary study endpoints included safety & PK. Plasma VEGF receptor & ligand concentrations were measured by ELISA & antitumor activity was assessed by CT scan. Results: 77 pts (57 M, 20 F; mean age 54.3 yrs) w/ chemorefractory solid tumors (22 CRC, 12 NSCLC, 12 sarcoma, 6 RCC,25 other) were enrolled. The rate of grade 3/4 AEs increased at doses above 100 mg w/hypertension & fatigue occurring in 18 % & 12 % of pts, diarrhea (9%) & thrombocytopenia (5%). The MTD was determined to be 100 mg CD, which was well-tolerated w/ manageable G3 diarrhea (n=2/6). PK was generally dose-proportional; at 100 mg CD, Cmax = 255 ng/mL, Tmax = 3 h, C24h = 63 ng/mL. SU014813 decreased plasma VEGFR2 & R3 concentrations in a dose- dependent manner (50–200 mg doses) but rebounded off treatment (4/1 schedule). Plasma VEGF generally increased after treatment but effects were variable. Twelve pts had an objective response at =50 mg daily dose levels; 1 pt w/ RCC had CR (183 days [d]);11 pts had PR (2 RCC, 2 thymoma, 2 NSCLC, 1 CRC, 4 other)(median 235 d; range 35- 470); 14 pts had stable disease (SD; median 178 d, range 58–554). Seven other pts who did not meet RECIST response criteria had long disease stabilization (median 200 d; range 180 - 440). Conclusions: SU014813 has a manageable safety & tolerability profiles at the doses studied. The MTD & recommended Ph II dose were determined to be 100 mg CD, as SU014813 had linear PK, modulated plasma VEGF receptors consistent with RTK inhibition, & demonstrated encouraging preliminary activity w/ durable responses across several tumor types. [Table: see text]