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Randomized phase II study evaluating veliparib (ABT-888) with temozolomide in patients with metastatic melanoma

Lookup NU author(s): Professor Ruth Plummer


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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.Patients and 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.

Publication metadata

Author(s): Middleton MR, Friedlander P, Hamid O, Daud A, Plummer R, Falotico N, Chyla B, Jiang F, McKeegan E, Mostafa NM, Zhu M, Qian J, Mckee M, Luo Y, Giranda VL, McArthur GA

Publication type: Article

Publication status: Published

Journal: Annals of Oncology

Year: 2015

Volume: 26

Issue: 10

Pages: 2173-2179

Print publication date: 01/10/2015

Online publication date: 22/07/2015

Acceptance date: 10/07/2015

ISSN (print): 0923-7534

ISSN (electronic): 1569-8041

Publisher: Oxford University Press


DOI: 10.1093/annonc/mdv308


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