R1530 is a multikinase inhibitor with both antitumor and antiangiogenic properties currently in clinical Phase I testing. The antitumor activity is mediated by its ability to disrupt cell division producing marked polyploidy and subsequent apoptosis, while the antiangiogenic activity is driven by potent inhibition of VEGFR1, 2, 3; PDGFRβ, Flt-3, and FGFR1, 2. The objective of the current study was to establish breadth of anti-tumor activity for R1530 in a variety of human xenograft models, and included HCT116 colorectal carcinoma, LoVo colorectal adenocarcinoma, 22rv1 androgen-independent prostate carcinoma, A549 non-small cell lung carcinoma and MDA-MB-435 estrogen-independent breast ductal adenocarcinoma. For these studies, animals were dosed daily at either 25 and 50 mg/kg, or 1.56 and 50 mg/kg. R1530 dosed once daily had a significant growth inhibitory effect in all models tested, with regression observed in all models treated at the optimal dose (OD) of 50 mg/kg qd. Partial rather than full regressions predominated in all models except the A549 model, where 6/9 full regressions were observed after three weeks of treatment. In the three models where ½ OD (25 mg/kg) R1530 was tested, regression was observed in two out of the three models (LoVo, MDA-MB-435) with the third (22rv1) yielding 98% tumor growth inhibition (TGI). There was a biologically significant increase in survival (≥ 25%) in all groups dosed with 25 or 50 mg/kg R1530 regardless of the xenograft model tested. The most impressive increased lifespan (ILS) with R1530 treatment was observed in the MDA-MB-435 model, where an impressive 163% and 233% ILS were observed in the 25 and 50 mg/kg treated groups. R1530 can be dosed once daily with comparable anti-tumor activity across a broad range of human xenograft models. These data support the potential for R1530 to demonstrate anti-tumor activity in the clinical setting.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA