title: Randomized phase II study evaluating veliparib (ABT-888) with temozolomide in patients with metastatic melanoma.
abstract: BACKGROUND
  Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models.
  
  
  METHODS
  In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).
  
  
  RESULTS
  Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0-5.5), 3.6 (1.9-4.1), and 2 (1.9-3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0-13.1), 13.6 (11.4-15.9), and 12.9 (9.8-14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively.
  
  
  CONCLUSIONS
  Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.
authors.affiliation: Department of Oncology, University of Oxford, Churchill Hospital, Oxford, UK mark.middleton@oncology.ox.ac.uk.
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Hematology and Medical Oncology, The Mount Sinai Medical Center, New York.
authors.forename: P
authors.initials: P
authors.lastname: Friedlander
authors.affiliation: Experimental Therapeutics/Immunotherapy, The Los Angeles Clinic and Research Institute, Los Angeles.
authors.forename: O
authors.initials: O
authors.lastname: Hamid
authors.affiliation: University of California San Francisco Medical Center, University of California, San Francisco, USA.
authors.forename: A
authors.initials: A
authors.lastname: Daud
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: N
authors.initials: N
authors.lastname: Falotico
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: B
authors.initials: B
authors.lastname: Chyla
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: F
authors.initials: F
authors.lastname: Jiang
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: E
authors.initials: E
authors.lastname: McKeegan
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Mostafa
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: M
authors.initials: M
authors.lastname: McKee
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.affiliation: AbbVie Inc., North Chicago, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Giranda
authors.affiliation: Divisions of Cancer Medicine/Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011379:Prognosis; D015996:Survival Rate; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; D000077204:Temozolomide
keywords: melanoma; metastasis; poly ADP-ribose polymerase inhibitor