A Phase II Double-Blinded, Randomized, Placebo-Controlled Study of Indoximod in Combination With a Taxane Chemotherapy in Metastatic Breast Cancer

It is estimated that 232,340 US women will be diagnosed with and 40,030 women will die of breast cancer in 2013. Metastatic breast cancer is a terminal condition and treatments are palliative in nature. The median survival for patients with metastatic breast cancer is approximately 2.5 years. The standard therapies currently in use include anti-estrogen therapies (anastrazole, letrozole, fulvestrant, tamoxifen), chemotherapy agents (taxanes, capecitabine, navelbine, gemcitabine, eribulin, ixabepilone), targeted therapies (trastuzumab, lapatinib), and supportive care agents (zolendronic acid, denosumab). While breast cancer typically responds well to treatment, the response is transient and their disease becomes more refractory with continued therapy. Also, quality of life is a significant issue for these patients as many of these therapies are associated with significant side effects. Well tolerated, novel agents which improve the efficacy of existing chemotherapy agents would prove quite useful in managing metastatic breast cancer. Preclinical data derived from MMTV-Neu mice with autochthonous tumors studied the interaction between indoximod and various chemotherapeutic agents. Mice with 5-10mm tumors were enrolled into control and treatment groups. Mice were treated with indoximod alone, chemotherapy alone (paclitaxel, doxorubicin, cyclophosphamide, and others), and the combination of indoximod and chemotherapy. treatment with indoximod or paclitaxel alone caused retardation of tumor growth in this model but no regressions were seen. the combination of indoximod plus paclitaxel caused 30% tumor regression and histologically there was significantly enhanced tumor cell death with the combination versus either agent alone. This synergism was abrogated when the mice underwent CD4+ T cell depletion prior to treatment with the combination, suggesting the immune response played a role in the observed effect. Based on this data and other reports suggesting systemic immunomodulating drugs like indoximod can synergize with chemotherapy agents such as taxanes, the decision was made to devise this combination of therapy of docetaxel or paclitaxel with indoximod in metastatic breast cancer.