title: Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer.
abstract: Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.affiliation: The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Wade
authors.affiliation: Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.affiliation: University of California Davis Cancer Center, Davis, CA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Allen
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Geraldine O'Sullivan
authors.initials: GO
authors.lastname: Coyne
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA. doroshoj@mail.nih.gov.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage; D018592:Cross-Over Studies; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003520:Cyclophosphamide
keywords: BRCA; DNA damage repair; HR defect; Metronomic cyclophosphamide; PARP inhibition