Antitumor activity of OSI-930, a novel multi-targeted tyrosine kinase inhibitor, in combination with standard chemotherapeutics in preclinical cancer models

677 The full potential and optimal utilization of targeted kinase inhibitors in combination with standard chemotherapeutic regimens has yet to be realized. OSI-930 potently inhibited the closely-related kinases Kit, KDR, and PDGFRβ in cell-based assays (IC 50 values . A FOLFOX-like regimen (5-FU/ oxaliplatin) was selected for combination studies with OSI-930 in two human CRC models, SW48 and COLO 205. 5-FU was administered at 20 mg/kg IV Day 1-5, oxaliplatin at 10 mg/kg IP on Day 1, and vehicle or OSI-930 200 mg/kg PO administered as maintenance therapy Day 8-21. Treatment with maintenance OSI-930 resulted in enhanced tumor growth inhibition (TGI) and growth delay (GD) compared to vehicle maintenance in both tumor models (SW48: TGI=84.4% compared to 68.9%, GD=6.8 days over vehicle; COLO 205: TGI=70.8% compared to 28.4%, GD=12.4 days over vehicle). In a separate COLO 205 study, OSI-930 administered at 100 mg/kg PO either concomitantly (Day 1-14) or as maintenance therapy (Day 8-21) improved tumor growth delay by 2-3 fold and increased TGI by 15-20% compared to vehicle maintenance. Both dosing schedules were well-tolerated with body weight loss in both groups