Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas

Shivaani Kummar, Alice Chen, Jiuping Ji, Yiping Zhang, Joel M Reid, Matthew Ames, Lee Jia, Marcie Weil, Giovanna Speranza, Anthony J. Murgo, Robert Kinders, Lihua Wang, Ralph E. Parchment, John Carter, Howard Stotler, Larry Rubinstein, Melinda Hollingshead, Giovanni Melillo, Yves Pommier, William BonnerJoseph E. Tomaszewski, James H. Doroshow

Research output: Contribution to journalArticle

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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 γH2AX 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/m2/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 γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan.Weshow 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.

Original languageEnglish (US)
Pages (from-to)5626-5634
Number of pages9
JournalCancer Research
Volume71
Issue number17
DOIs
StatePublished - Sep 1 2011

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Topotecan
Lymphoma
Neoplasms
Type I DNA Topoisomerase
Maximum Tolerated Dose
Pharmacokinetics
DNA Damage
Appointments and Schedules
Topoisomerase I Inhibitors
Poly Adenosine Diphosphate Ribose
Circulating Neoplastic Cells
veliparib
Poly(ADP-ribose) Polymerase Inhibitors
Genetic Markers
Heterografts
Nude Mice
Blood Cells
Urine
Biopsy
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. / Kummar, Shivaani; Chen, Alice; Ji, Jiuping; Zhang, Yiping; Reid, Joel M; Ames, Matthew; Jia, Lee; Weil, Marcie; Speranza, Giovanna; Murgo, Anthony J.; Kinders, Robert; Wang, Lihua; Parchment, Ralph E.; Carter, John; Stotler, Howard; Rubinstein, Larry; Hollingshead, Melinda; Melillo, Giovanni; Pommier, Yves; Bonner, William; Tomaszewski, Joseph E.; Doroshow, James H.

In: Cancer Research, Vol. 71, No. 17, 01.09.2011, p. 5626-5634.

Research output: Contribution to journalArticle

Kummar, S, Chen, A, Ji, J, Zhang, Y, Reid, JM, Ames, M, Jia, L, Weil, M, Speranza, G, Murgo, AJ, Kinders, R, Wang, L, Parchment, RE, Carter, J, Stotler, H, Rubinstein, L, Hollingshead, M, Melillo, G, Pommier, Y, Bonner, W, Tomaszewski, JE & Doroshow, JH 2011, 'Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas', Cancer Research, vol. 71, no. 17, pp. 5626-5634. https://doi.org/10.1158/0008-5472.CAN-11-1227
Kummar, Shivaani ; Chen, Alice ; Ji, Jiuping ; Zhang, Yiping ; Reid, Joel M ; Ames, Matthew ; Jia, Lee ; Weil, Marcie ; Speranza, Giovanna ; Murgo, Anthony J. ; Kinders, Robert ; Wang, Lihua ; Parchment, Ralph E. ; Carter, John ; Stotler, Howard ; Rubinstein, Larry ; Hollingshead, Melinda ; Melillo, Giovanni ; Pommier, Yves ; Bonner, William ; Tomaszewski, Joseph E. ; Doroshow, James H. / Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. In: Cancer Research. 2011 ; Vol. 71, No. 17. pp. 5626-5634.
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AU - Ames, Matthew

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