Phase 2 Study of Neoadjuvant Treatment with Nov-002 in Combination with Doxorubicin and Cyclophosphamide Followed By Docetaxel in Patients with HER-2 Negative Clinical Stage II-IIIc Breast Cancer

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC→T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16% to 32% with NOV-002 plus AC→T (α=0.05, β=80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 16 achieved a pCR (40%), meeting the primary endpoint of the trial. Lower circulating levels of MDSCs at baseline and cycle 8 were associated with a pCR (P=0.02). Concurrent NOV-002 resulted in pCR rates for AC→T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (p=0.02). Further evaluation of NOV-002 in a randomized study is warranted