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Ann Oncol. 2015 Oct;26(10):2173-9. doi: 10.1093/annonc/mdv308. Epub 2015 Jul 22.

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

Author information

1
Department of Oncology, University of Oxford, Churchill Hospital, Oxford, UK mark.middleton@oncology.ox.ac.uk.
2
Hematology and Medical Oncology, The Mount Sinai Medical Center, New York.
3
Experimental Therapeutics/Immunotherapy, The Los Angeles Clinic and Research Institute, Los Angeles.
4
University of California San Francisco Medical Center, University of California, San Francisco, USA.
5
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
6
AbbVie Inc., North Chicago, USA.
7
Divisions of Cancer Medicine/Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.

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.

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.

KEYWORDS:

melanoma; metastasis; poly ADP-ribose polymerase inhibitor

PMID:
26202595
DOI:
10.1093/annonc/mdv308
[Indexed for MEDLINE]

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