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

A. J. Montero, C. M. Diaz-Montero, Y. E. Deutsch, J. Hurley, Leonidas Koniaris, T. Rumboldt, S. Yasir, M. Jorda, E. Garret-Mayer, E. Avisar, J. Slingerland, O. Silva, C. Welsh, K. Schuhwerk, P. Seo, M. D. Pegram, S. Glück

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
JournalBreast Cancer Research and Treatment
Volume132
Issue number1
DOIs
StatePublished - Feb 2012
Externally publishedYes

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docetaxel
Neoadjuvant Therapy
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Drug Therapy
Neoplasms
NOV 002
Glutathione Disulfide
Blood Cell Count

Keywords

  • Anthracycline
  • Breast cancer
  • Glutathione analog
  • MDSC
  • Myeloid derived suppressor cells
  • Neoadjuvant
  • NOV-002
  • Pathologic complete response
  • Phase 2
  • Taxane

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Montero, A. J.; Diaz-Montero, C. M.; Deutsch, Y. E.; Hurley, J.; Koniaris, Leonidas; Rumboldt, T.; Yasir, S.; Jorda, M.; Garret-Mayer, E.; Avisar, E.; Slingerland, J.; Silva, O.; Welsh, C.; Schuhwerk, K.; Seo, P.; Pegram, M. D.; Glück, S.

In: Breast Cancer Research and Treatment, Vol. 132, No. 1, 02.2012, p. 215-223.

Research output: Contribution to journalArticle

Montero, AJ, Diaz-Montero, CM, Deutsch, YE, Hurley, J, Koniaris, L, Rumboldt, T, Yasir, S, Jorda, M, Garret-Mayer, E, Avisar, E, Slingerland, J, Silva, O, Welsh, C, Schuhwerk, K, Seo, P, Pegram, MD & Glück, S 2012, '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', Breast Cancer Research and Treatment, vol. 132, no. 1, pp. 215-223. https://doi.org/10.1007/s10549-011-1889-0
Montero, A. J. ; Diaz-Montero, C. M. ; Deutsch, Y. E. ; Hurley, J. ; Koniaris, Leonidas ; Rumboldt, T. ; Yasir, S. ; Jorda, M. ; Garret-Mayer, E. ; Avisar, E. ; Slingerland, J. ; Silva, O. ; Welsh, C. ; Schuhwerk, K. ; Seo, P. ; Pegram, M. D. ; Glück, S. / 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. In: Breast Cancer Research and Treatment. 2012 ; Vol. 132, No. 1. pp. 215-223.
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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.",
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