title: A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study.
abstract: BACKGROUND
  Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA).
  
  
  METHODS
  Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha=10% (at a 10% assumed null response probability).
  
  
  RESULTS
  The median age of the 50 eligible patients was 57years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n=3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events >10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18months.
  
  
  CONCLUSIONS
  The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation.
authors.affiliation: Dept. of Gynecologic Oncology & Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rcoleman@mdanderson.org.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: NRG Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.affiliation: Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bell-McGuinn
authors.affiliation: Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.affiliation: University of Washington, Dept. of OB/GYN, Seattle, WA 98195, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Gray
authors.affiliation: University of California Irvine Medical Center, Irvine Chao Family Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Orange, CA 92868, USA.
authors.forename: Krishnansu S
authors.initials: KS
authors.lastname: Tewari
authors.affiliation: Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Rubin
authors.affiliation: Yale University School of Medicine, Division of GYN Oncology, New Haven, CT 06520, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.affiliation: Palo Alto Medical Foundation, San Francisco, CA 94118, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Investigational Drug Branch Cancer Therapy Evaluation Program, Bethesda, MD 20892, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: University of Washington and the Fred Hutchinson Cancer Research Center, Puget Sound Oncology Consortium, Seattle, WA 98109, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001562:Benzimidazoles; C521013:veliparib
keywords: BRCA1, BRCA2 mutation; Ovarian cancer; PARP inhibitor; Phase II trial; Toxicity; Veliparib
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