RT Journal Article
SR Electronic
T1 Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 5626
OP 5634
DO 10.1158/0008-5472.CAN-11-1227
VO 71
IS 17
A1 Kummar, Shivaani
A1 Chen, Alice
A1 Ji, Jiuping
A1 Zhang, Yiping
A1 Reid, Joel M.
A1 Ames, Matthew
A1 Jia, Lee
A1 Weil, Marcie
A1 Speranza, Giovanna
A1 Murgo, Anthony J.
A1 Kinders, Robert
A1 Wang, Lihua
A1 Parchment, Ralph E.
A1 Carter, John
A1 Stotler, Howard
A1 Rubinstein, Larry
A1 Hollingshead, Melinda
A1 Melillo, Giovanni
A1 Pommier, Yves
A1 Bonner, William
A1 Tomaszewski, Joseph E.
A1 Doroshow, James H.
YR 2011
UL http://cancerres.aacrjournals.org/content/71/17/5626.abstract
AB 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. 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. ©2011 AACR.