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

Abstract

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, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. 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.

Figure 1. Treatment schema for NEO-NOVO trial

Figure 2. Longitudinal hematologic indices on study patients

Weekly complete blood counts were obtained on all patients. Data shown for hemoglobin (A), total white blood count (B), absolute neutrophil (C), and lymphocyte (D) counts. Black line represents the average and red lines denote 95% confidence intervals.

Figure 3. Correlation between myeloid derived suppressor cell (MDSC) levels and pCR in study patients

(A) FACS gating strategy for MDSCs. Circulating MDSC levels at baseline (B) and on cycle 1 day 8 (C), were significantly higher in patients who didn’t achieve a pCR after preoperative chemotherapy plus NOV-002

Figure 4. Kaplan-Meier plots of the probability of recurrence free survival by residual cancer burden (RCB) status