Abstract P1-11-05: Phase 2 Study of Neoadjuvant Treatment with Cellular Redox Modulator NOV-002 in Combination with Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC→T) in Patients with Stage II-III HER-2 (-) Breast Cancer
Authors: Montero AJ , Diaz CM , Slingerland J , Pegram M , Hurley J , Welsh CF , Avisar E , Seo P , Vogel CL , Garrett-Mayer E , Hermann V , Baker MK , Silva O , Koniaris L , Rodgers S , Schuhwerk K , Pazoles CJ , Moffat F , Cole DJ , Gluck S. 
Published: April 2011

Abstract
Background: 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 a range of cytotoxic chemotherapeutic regimens has been shown to increase their anti-tumor efficacy in several early phase oncology trials and in animal models. Pathological complete response (pCR) has been demonstrated to be associated with favorable overall survival in primary breast cancer, and neoadjuvant treatment of early breast cancer aims at achieving high rates of pCR. In patients with HER-2 (-) breast cancer pCR rates with anthracycline and taxane combinations have been reported to be approximately 10-20% depending on hormone receptor status. We conducted a clinical trial in HER-2 negative patients (pts) combining daily N0V-002 with AC→T. Methods: Women with newly diagnosed stages II-III HER-2 (-) breast cancer received AC x 4 [60/600 mg/m2] followed by T [100 mg/m2] x 4 every 3 weeks in conjunction with daily N0V-002 [60mg IV day 1 and subcutaneously days 2-21 of each cycle]. The primary endpoint is pCR, defined as: (i) ypN0, and (ii) ypT0 or presence of invasive tumor &lt;10mm.
Sample size (n=46 total patients) was calculated using a Simon 2-stage optimal design assuming a doubling of the historical pCR rate with the addition of NOV-002 to AC→T from a p0 of 0.16 to a p1 of 0.32. If a total of 12 or more patients experience a pCR by the end of the trial, then the treatment regimen will be declared active. The calculation assumes an alpha of 0.05 and 80% power.
Results: A total of 39 pts have been enrolled to date across three study sites, with 31 patients having completed chemotherapy and undergone surgery. One patient dropped out during cycle 1 and was not assessable for response; 5 are currently receiving chemotherapy; and 2 patients have completed all chemotherapy, but have not yet undergone surgery. A total of 292 chemotherapy cycles have been administered, with 92% of all patients being able to complete all 8 cycles of planned chemotherapy. Of the 31 evaluable patients, 12 achieved a pCR (39%), meeting the primary endpoint of the trial. In patients with residual invasive primary breast tumor &lt;10mm and ypN0 (19%) mean residual tumor size was 4.4 mm. Interestingly, of the 17 patients with biopsy-proven axillary involvement, 4 (23%) had no residual invasive tumor in axillary nodes at time of surgery. In 26 patients with estrogen positive breast cancer, which is least sensitive to chemotherapy, 42% achieved a pCR. The most common toxicities included: nausea, sensory neuropathy, emesis, fatigue, and hand-foot syndrome. Conclusions: The addition of NOV-002 has to date resulted in a doubling of previously published pCR rates with AC→T in HER-2 (-) breast cancer patients. Subsequent investigation of NOV-002 in conjunction with neoadjuvant chemotherapy in breast cancer is warranted. Updated clinical data on all 39 patients as well as immunologic correlative markers will be presented.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-05.