title: Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/or BRCA Mutation-Associated Breast Cancer.
abstract: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.
  
  
  
  A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.
  
  
  
  Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1-6.7).
  
  
  
  Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Clin Cancer Res; 22(12); 2855-64. ©2016 AACR.
authors.affiliation: University of California, Davis, California. erodler@ucdavis.edu.
authors.forename: Eve T
authors.initials: ET
authors.lastname: Rodler
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Kurland
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Melissa
authors.initials: M
authors.lastname: Griffin
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Peggy
authors.initials: P
authors.lastname: Porter
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Yeh
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Vijayakrishna K
authors.initials: VK
authors.lastname: Gadi
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jamie
authors.initials: J
authors.lastname: Guenthoer
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Larissa
authors.initials: L
authors.lastname: Korde
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kiesel
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Linden
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Swisher
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chai
authors.affiliation: AbbVie Laboratories, North Chicago, Illinois.
authors.forename: Stacie
authors.initials: S
authors.lastname: Shepherd
authors.affiliation: AbbVie Laboratories, North Chicago, Illinois.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giranda
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Specht
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D024682:BRCA2 Protein / Q000235:genetics*; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004260:DNA Repair / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014747:Vinblastine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D024682:BRCA2 Protein; D001562:Benzimidazoles; D002945:Cisplatin; D011064:Poly Adenosine Diphosphate Ribose; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D044767:Ubiquitin-Protein Ligases; D014747:Vinblastine; D000077235:Vinorelbine; C551750:BRCA2 protein, human; C521013:veliparib; C111164:BRAP protein, human; C508053:ERBB2 protein, human