Preclinical testing of a novel regimen of capecitabine (C) in combination with bevacizumab (B) and trastuzumab (T) in a breast cancer xenograft model

Abstract

1049 Background: Mathematical methods applied to xenograft breast cancer models have determined that the maximum impact of C therapy occurs after ∼7 days (7d) of treatment (Norton AACR 2005). The model predicts that doses of C beyond 7d will contribute to toxicity without additional antitumor benefit. The tolerability and anti-tumor activity of C 7d on/7d off (7/7) in female nude mice bearing KPL-4 breast cancer xenografts has been established (SABCS 2006). We now report preclinical models of C7/7 with targeted therapies. Methods: We evaluated the tumor growth inhibition (TGI%) and increase in life span (ILS%) of C7/7 and B with or without T in female nude mice bearing KPL-4, HER2+ breast cancer xenografts. C at maximum tolerated dose (MTD) and ½MTD were tested in combination with conventional doses of the antibodies. Results: C7/7 at MTD is well tolerated in combination with conventional dose B + T. No toxicity was observed at any dose level. The addition of B ± T to C7/7 monotherapy significantly improves TGI%. Survival is significantly prolonged for the combination of C7/7 MTD with B ± T. Comparative results for C7/7 at MTD and ½ MTD are shown in the Table . Additional comparative data will be shown at the meeting. Assessment of ILS% is ongoing for the triplet C7/7 + B + T but has exceeded 463% and &gt;152 days. Conclusions: The improvement in response and survival shown here supports the study of combination C7/7 with B and T. Combinations with B and anti-HER2 therapy will be tested in the clinical, Phase II program at MSKCC. [Table: see text] [Table: see text] </jats:p