Preclinical chemotherapy with the VEGFR-2 and PDGFR inhibitor, BAY 57-9352, in combination with Capecitabine and Paclitaxel

Abstract

2030

BAY 57-9352 is an orally active, small molecule inhibitor of VEGFR-2 and PDGFR-b tyrosine kinases, which is currently in Phase I clinical trials. BAY 57-9352 blocks tumor growth through the inhibition of these key regulators of tumor angiogenesis. It exhibits a broad-spectrum of activity as a single agent in multiple human tumor xenograft models representing breast, colon, prostate and lung cancer. The clinical development of BAY 57-9352 is anticipated to include combination chemotherapy with the current standards of care for a variety of histological types of cancer. In the current studies, we have examined the anti-tumor activity and tolerability of BAY 57-9352 when co-administered with either capecitabine (Xeloda® ) or paclitaxel (Taxol® ). The anti-tumor efficacy and tolerability of BAY 57-9352 in combination with capecitabine or paclitaxel were examined using subcutaneous Colo-205 human colorectal cancer or H460 human non-small cell lung cancer xenograft models, respectively, implanted in female athymic (NCr-nu/nu) mice. In two studies combining BAY 57-9352 with capecitabine, both agents were administered p.o. for 9 or 10 days. When combined with paclitaxel, BAY 57-9352 was administered p.o. for 9 days and paclitaxel was administered concurrently (i.v.) for the first 5 days. Efficacy was assessed as the days delay in tumor growth to reach a specified size (TGD). BAY 57-9352 (60 mg/kg, p.o.) and capecitabine (500 mg/kg, p.o.) demonstrated significant anti-tumor activity following once daily administration as single agents in the Colo-205 model with an average TGD of 16 and 30 days, respectively. Combination of these agents showed an average TGD of 40 days with no toxicity. Combination of BAY 57-9352 with paclitaxel required reduction of BAY 57-9352 from 60 mg/kg to 40 mg/kg to achieve acceptable tolerability. In the H460 model, BAY 57-9352 (40 mg/kg, p.o.) and paclitaxel (15 mg/kg, i.v.) exhibited anti-tumor activity as single agents with a TGD of 6 days and 10 days, respectively. When combined, these agents produced a TGD of 14 days and demonstrated acceptable toxicity. In all studies, the combination of BAY 57-9352 with capecitabine or paclitaxel was at least as effective as the individual agents administered alone. The results of these studies support the combination of BAY 57-9352 with either capecitabine or paclitaxel in clinical studies with these agents.