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Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas

  1. Author:
    Kummar, S.
    Chen, A.
    Ji, J. P.
    Zhang, Y. P.
    Reid, J. M.
    Ames, M.
    Jia, L.
    Weil, M.
    Speranza, G.
    Murgo, A. J.
    Kinders, R.
    Wang, L. H.
    Parchment, R. E.
    Carter, J.
    Stotler, H.
    Rubinstein, L.
    Hollingshead, M.
    Melillo, G.
    Pommier, Y.
    Bonner, W.
    Tomaszewski, J. E.
    Doroshow, J. H.

  2. Author Address

    [Doroshow, JH] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, JH] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Ji, JP; Zhang, YP; Kinders, R; Wang, LH; Parchment, RE; Carter, J; Stotler, H; Melillo, G] NCI, Sci Applicat Int Corp Frederick Inc, Appl Dev Res Support Directorate, Frederick, MD 21701 USA. [Reid, JM; Ames, M] Mayo Clin, Rochester, MN USA.;Doroshow, JH (reprint author), NCI, Ctr Canc Res, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA;doroshoj@mail.nih.gov
    1. Year: 2011
    2. Date: Sep
  2. Journal: Cancer Research
    1. 71
    2. 17
    3. Pages: 5626-5634
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker gamma H2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m(2)/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in gamma H2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic. Cancer Res; 71(17);5626-34. (C) 2011 AACR.

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External Sources

  1. View Full Text
  2. DOI: 10.1158/0008-5472.can-11-1227
  3. View record in Web of Science®
  4. WOS: 000294454700006

Library Notes

  1. Fiscal Year: FY2011-2012
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