Abstract B14: The broad spectrum antitumor efficacy and tolerability of the RTK inhibitor, linifanib (ABT‐869) alone and in combination with various cytotoxic therapies

The RTKI, linifanib (ABT‐869), is a potent inhibitor of vascular endothelial growth factor (VEGF) as well as platelet‐derived growth factor (PDGF) receptors and is currently in Phase 1 – 2 clinical trials. It exhibits potent inhibition of mutant kinases, such as fms‐like tyrosine kinase 3 (FLT3), c‐kit (CD117) and colony stimulating factor‐1 receptor (CSF1R). Hepatocellular carcinoma (HCC), renal cell carcinoma (RCC) and prostate carcinoma (PC) are known hypervascular/angiogenic tumor types. The role of the vascular process in HCC tumor progression, HIF‐mediated induction of VEGF in many VHL‐deleted RCCs, as well as PDGF expression in PC, highlight the potential of anti angiogenic therapy as an attractive therapeutic strategy. Previous studies have shown potent anti‐tumor and anti‐angiogenic activity against a spectrum of xenografts (HCC, RCC, PC, fibrosarcoma and NSCLC). Thus, the ability of linifanib to inhibit tumor growth in known hypervascular/angiogenic tumors suggests on‐mechanism activity. Linifanib was well tolerated in the clinic and activity was observed in HCC, NSCLC, and renal carcinoma. The ability to be used as combination treatment regimen without excessive impact on tolerability is of great interest to increase clinical efficacy and positively impact patient outcomes. In this study, we sought to evaluate the activity of linifanib in a broad spectrum of xenograft models (breast, colon, HNSCC, liver, NSCLC, SCLC, ovarian and pancreatic), alone or in combination with various cytotoxic therapies (carbotaxol, irinotecan, radiation, 5‐FU/leucovorin, gemcitabine and oxaliplatin). The doses used for ABT‐869 were clinically relevant. For the cytotoxic therapies, doses were determined both by clinical schedules and tolerability as single agents in mice. In all studies, linifanib (25, 12.6, 6.25, p.o., b.i.d.x21) was well tolerated alone or in combination with cytotoxic therapy and demonstrated no exacerbation of cytotoxic agent toxicity as assessed by animal health observations. Significant anti‐tumor efficacy (measured by percent tumor growth inhibition, % TGI) was observed with linifanib monotherapy and the combination with cytotoxic therapies showed significant efficacy over linifanib or cytotoxic therapies alone. Further, lower doses of linifanib in combination with cytotoxic agents achieved similar efficacy as higher doses of linifanib alone. These studies demonstrate the significant activity of linifanib or linifanib in combination with multiple cytotoxic therapies in a spectrum of models representing multiple histological types and provide a rationale for future clinical investigations. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B14.