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, Judith Hurley, L. G. Koniaris, T. Rumboldt, S. Yasir, Merce Jorda, E. Garret-Mayer, Eli Avisar, Joyce M Slingerland, O. Silva, Catherine Welsh, K. Schuhwerk, Pearl H Seo, M. D. Pegram, S. Glück

Research output: Contribution to journalArticle

50 Citations (Scopus)

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
Pages (from-to)215-223
Number of pages9
JournalBreast Cancer Research and Treatment
Volume132
Issue number1
DOIs
StatePublished - Feb 1 2012

Fingerprint

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, Judith; Koniaris, L. G.; Rumboldt, T.; Yasir, S.; Jorda, Merce; Garret-Mayer, E.; Avisar, Eli; Slingerland, Joyce M; Silva, O.; Welsh, Catherine; Schuhwerk, K.; Seo, Pearl H; Pegram, M. D.; Glück, S.

In: Breast Cancer Research and Treatment, Vol. 132, No. 1, 01.02.2012, p. 215-223.

Research output: Contribution to journalArticle

@article{8bc3e4f78d1a44b2aeb610639e49b4ea,
title = "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.",
keywords = "Anthracycline, Breast cancer, Glutathione analog, MDSC, Myeloid derived suppressor cells, Neoadjuvant, NOV-002, Pathologic complete response, Phase 2, Taxane",
author = "Montero, {A. J.} and Diaz-Montero, {C. M.} and Deutsch, {Y. E.} and Judith Hurley and Koniaris, {L. G.} and T. Rumboldt and S. Yasir and Merce Jorda and E. Garret-Mayer and Eli Avisar and Slingerland, {Joyce M} and O. Silva and Catherine Welsh and K. Schuhwerk and Seo, {Pearl H} and Pegram, {M. D.} and S. Gl{\"u}ck",
year = "2012",
month = "2",
day = "1",
doi = "10.1007/s10549-011-1889-0",
language = "English",
volume = "132",
pages = "215--223",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - 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

AU - Montero, A. J.

AU - Diaz-Montero, C. M.

AU - Deutsch, Y. E.

AU - Hurley, Judith

AU - Koniaris, L. G.

AU - Rumboldt, T.

AU - Yasir, S.

AU - Jorda, Merce

AU - Garret-Mayer, E.

AU - Avisar, Eli

AU - Slingerland, Joyce M

AU - Silva, O.

AU - Welsh, Catherine

AU - Schuhwerk, K.

AU - Seo, Pearl H

AU - Pegram, M. D.

AU - Glück, S.

PY - 2012/2/1

Y1 - 2012/2/1

N2 - 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.

AB - 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.

KW - Anthracycline

KW - Breast cancer

KW - Glutathione analog

KW - MDSC

KW - Myeloid derived suppressor cells

KW - Neoadjuvant

KW - NOV-002

KW - Pathologic complete response

KW - Phase 2

KW - Taxane

UR - http://www.scopus.com/inward/record.url?scp=84857916510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857916510&partnerID=8YFLogxK

U2 - 10.1007/s10549-011-1889-0

DO - 10.1007/s10549-011-1889-0

M3 - Article

C2 - 22138748

AN - SCOPUS:84857916510

VL - 132

SP - 215

EP - 223

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -