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.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Avenue, Suite 3510 (D8-4), Miami, FL 33136, USA. amontero2@med.miami.edu
authors.forename: A J
authors.initials: AJ
authors.lastname: Montero
authors.forename: C M
authors.initials: CM
authors.lastname: Diaz-Montero
authors.forename: Y E
authors.initials: YE
authors.lastname: Deutsch
authors.forename: J
authors.initials: J
authors.lastname: Hurley
authors.forename: L G
authors.initials: LG
authors.lastname: Koniaris
authors.forename: T
authors.initials: T
authors.lastname: Rumboldt
authors.forename: S
authors.initials: S
authors.lastname: Yasir
authors.forename: M
authors.initials: M
authors.lastname: Jorda
authors.forename: E
authors.initials: E
authors.lastname: Garret-Mayer
authors.forename: E
authors.initials: E
authors.lastname: Avisar
authors.forename: J
authors.initials: J
authors.lastname: Slingerland
authors.forename: O
authors.initials: O
authors.lastname: Silva
authors.forename: C
authors.initials: C
authors.lastname: Welsh
authors.forename: K
authors.initials: K
authors.lastname: Schuhwerk
authors.forename: P
authors.initials: P
authors.lastname: Seo
authors.forename: M D
authors.initials: MD
authors.lastname: Pegram
authors.forename: S
authors.initials: S
authors.lastname: Glück
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D004338:Drug Combinations; D005260:Female; D019803:Glutathione Disulfide / Q000008:administration & dosage; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D053208:Kaplan-Meier Estimate; D008408:Mastectomy; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003520:Cyclophosphamide; D000077143:Docetaxel; D004317:Doxorubicin; D004338:Drug Combinations; D019803:Glutathione Disulfide; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C529375:NOV 002; C508053:ERBB2 protein, human