Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: Results of a phase 0 trial

Abstract

3518 Background: Inhibition of PARP activity sensitizes tumor cells to the effects of DNA damaging agents. We conducted a phase 0 pharmacokinetic (PK) and pharmacodynamic (PD) study of ABT-888, an oral inhibitor of PARP. Methods: The objectives were to determine a dose range at which ABT-888 inhibits PARP in tumor tissue and in peripheral blood mononuclear cells (PBMC); and the PK of ABT-888. Patients with advanced solid tumors refractory to at least one line of therapy were eligible; patients with CLL or follicular lymphomas were also eligible if standard therapy was not currently indicated. A single oral dose of ABT-888 was administered per patient, dose escalations were planned in cohorts of 3 patients each (10 mg, 25 mg, 50 mg, 100 mg, and 150 mg). PBMC and tumor sampling were performed before and after drug administration for real time PK and PD analyses. All patients underwent PBMC sampling; tumor biopsies were planned once significant inhibition of PARP activity in PBMCs was seen in 1 of 3 patients in a cohort or plasma Cmax of 210 nM was achieved in at least 1 patient. Tumor biopsies were performed at baseline in the week prior to drug administration and then 3–6 hours post drug administration. Significant inhibition of PARP activity was defined as at least 0.69 reduction on the log scale, which also satisfied statistical significance. Results: A total of 6 patients have been studied so far, 3 each for the 10 mg and 25 mg cohorts. No treatment related adverse events have been observed. Target Cmax was exceeded in the first cohort, all patients in the next cohort underwent tumor biopsies in addition to PBMC sampling. A trend towards inhibition of PARP activity in PBMCs was observed in the first cohort. Significant inhibition of PAR levels was observed in tumor biopsies from all 3 patients in the second cohort (92%, 99%, 100% reductions respectively, as compared to baseline). Greater than 85% reduction of PAR levels was observed in PBMCs from 2 of the 3 patients in the second cohort (one patient was not evaluable). Conclusions: ABT-888 is orally bioavailable and inhibits PARP activity in PBMCs and tumor cells. Target assay feasibility was established in human samples. Funded in part by NCI Contract N01-CO-12400 No significant financial relationships to disclose.