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 poly(ADP-ribose) polymerase (PARP inhibitor), in combination with topotecan, a topoisomerase I–targeted agent, was performed 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 (PBMCs). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to co-administer 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/day and ABT-888 10 mg BID on days 1–5 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 demonstrate 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.

Mutations of human DNA topoisomerase I at poly(ADP-ribose) binding sites: modulation of camptothecin activity by ADP-ribose polymers

“…Anyhow, the addition of PARs to the reaction mixture enhances the religation rate similarly to the wild-type protein (lanes 10-13). CPT inhibits in both enzymes the religation step (lanes 6-9) that is restored in presence of PARs (lanes [14][15][16][17], as also shown by the quantitative plot of Figure 4B. These findings are consistent with the antagonistic effects exerted by PARs on the activity of hTop1 poisons [10].…”

“…Accordingly, PARP inhibitors remove the antagonistic effect exerted by PARs on the mechanism of action of hTop1 poisons, increasing the formation of persistent DNA breaks. Indeed, the combination of PARP inhibitors with the CPT derivatives irinotecan or topotecan resulted in synergistic antitumor effects in preclinical tumor models and is under evaluation in clinical trials for the treatment of a number of refractory malignancies [14][15][16][17][18][19] (www.clinicaltrials.gov).…”

Dynamic Regulation of Rad51 by E2F1 and p53 in Prostate Cancer Cells upon Drug-Induced DNA Damage under Hypoxia

“…*P , 0.05; **P , 0.01. et al, 2012). Enhanced DNA damage and antitumor activities were also reported in phase I studies with the veliapribtopotecan combination (Kummar et al, 2011) and the veliparib-irinotecan combination (LoRusso et al, 2011). Of note, neither phase I studies included prostate cancer patients.…”

PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway

“…These findings may have important clinical implications, because topoisomerase I poisons and DNA methylating agents such as TMZ are used in second-line chemotherapy regimens for Ewing sarcoma (22). However, increased host toxicity may limit the therapeutic window for such combinations, because there is preclinical and clinical evidence for enhanced normal tissue toxicity upon cotreatment with PARP inhibitors and TMZ or topoisomerase I inhibitors (12,16,25). PARP inhibitors also enhanced doxorubicin-, etoposide-, or ifosfamide-induced cytotoxicity in Ewing sarcoma cells, although less consistently.…”