Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts

SU101 (leflunomide, N-[4-(trifluoromethyl)-phenyl] 5-methylisoxazole-4-carb oxamide), an inhibitor of platelet-derived growth factor receptor signaling , has shown promising clinical activity in Phase I and II studies. Currentl y, SU101 in combination with cytotoxic agents is in late-stage clinical dev elopment for the treatment of cancers. In previous reports, efficacy in viv o versus varied tumor xenografts was observed. As part of the preclinical d evelopment of SU101 as a cancer therapy, the combination of SU101 with cyto toxic agents was studied in athymic mice bearing small, established, s.c. h uman tumor cell xenografts of glioblastoma (SF763T cells), lung (Calu-6 cel ls), or head and neck (KB cells) origin. In the SF763T model, the combinati on of SU101 with carmustine resulted in a statistically significant growth inhibition of 74% compared with the vehicle control; this combination was m ore effective than either agent alone. In the Calu-6 model, the combination of SU101, cisplatin, and etoposide resulted in a growth inhibition of 75% that was statistically greater than that of the vehicle-treated control gro up and groups treated with one or two agents. In the KB model, the combinat ion of SU101, 5-fluorouracil, and cisplatin resulted in a statistically sig nificant growth inhibition of 69% compared with tbe vehicle control. Treatm ent with one or two agents did not significantly inhibit growth in this mod el. Importantly, in addition to enhanced efficacy resulting from combinatio n therapies, the combination treatments tested were well tolerated, as evid enced by lack of mortality. These data suggest that SU101 in combination wi th cytotoxic agents may provide clinical benefit and warrant further clinic al investigation.