title: Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
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. 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.
authors.affiliation: Center for Cancer Research and Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew
authors.initials: M
authors.lastname: Ames
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Marcie
authors.initials: M
authors.lastname: Weil
authors.forename: Giovanna
authors.initials: G
authors.lastname: Speranza
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Robert
authors.initials: R
authors.lastname: Kinders
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Parchment
authors.forename: John
authors.initials: J
authors.lastname: Carter
authors.forename: Howard
authors.initials: H
authors.lastname: Stotler
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Giovanni
authors.initials: G
authors.lastname: Melillo
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: William
authors.initials: W
authors.lastname: Bonner
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000008:administration & dosage*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D059004:Topoisomerase I Inhibitors; C521013:veliparib; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases