title: Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer.
abstract: OBJECTIVE
  Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).
  
  
  METHODS
  Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.
  
  
  RESULTS
  Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.
  
  
  CONCLUSIONS
  This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.affiliation: Princess Margaret Hospital, University of Toronto, Ontario, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: The University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: University of California Davis Cancer Center, Davis, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Naughton
authors.affiliation: The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, Ohio.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Szabo
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ahrim
authors.initials: A
authors.lastname: Youn
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Allen
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Chih-Jian
authors.initials: CJ
authors.lastname: Lih
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Michele G
authors.initials: MG
authors.lastname: Mehaffey
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Walsh
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Paul M
authors.initials: PM
authors.lastname: McGregor
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: P Mickey
authors.initials: PM
authors.lastname: Williams
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Conley
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Simon
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland. doroshoj@mail.nih.gov.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C521013:veliparib; D003520:Cyclophosphamide