title: A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.
abstract: OBJECTIVE
  The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer.
  
  
  METHODS
  This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m²) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints.
  
  
  RESULTS
  Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy.
  
  
  CONCLUSIONS
  Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.
authors.affiliation: *Summa Cancer Institute, Summa Health System, Akron, OH; †NRG Oncology/Gynecologic Oncology Group Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY; ‡Case Western Reserve University, Cleveland, OH; §UT Southwestern Medical Center, Dallas, TX; ∥University Hospitals Case Medical Center, Cleveland, OH; ¶University of Washington, Seattle, WA; #University of Iowa, Iowa City, IA; **Decatur Memorial Hospital, Cancer Care Specialists of Central Illinois, Decatur, IL; ††Virginia Commonwealth University, Richmond, VA; and ‡‡Oklahoma University Health Science Center, Oklahoma City, OK.
authors.forename: Charles
authors.initials: C
authors.lastname: Kunos
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Dawn
authors.initials: D
authors.lastname: Dawson
authors.forename: Jayanthi S
authors.initials: JS
authors.lastname: Lea
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Zanotti
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Gray
authors.forename: David P
authors.initials: DP
authors.lastname: Bender
authors.forename: Perry P
authors.initials: PP
authors.lastname: Guaglianone
authors.forename: Jori S
authors.initials: JS
authors.lastname: Carter
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000032:analysis; D018450:Disease Progression; D005260:Female; D000069585:Filgrastim / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000737:chemistry / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000627:therapeutic use; D012264:Ribonucleotide Reductases / Q000032:analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000188:drug therapy*
chemical_list: D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D011994:Recombinant Proteins; C521013:veliparib; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D019772:Topotecan; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000069585:Filgrastim