Pharmacodynamic response in phase I combination study of ABT-888 and topotecan in adults with refractory solid tumors and lymphomas.

Abstract

2514 Background: Poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors such as ABT-888 may prevent efficient repair of DNA damage induced by topoisomerase 1 inhibitors and lead to double-strand breaks, which activate DNA-damage signaling pathways through phosphorylation of histone H2AX (γH2AX). We evaluated the pharmacodynamics (PD) of ABT-888 and topotecan alone and in combination through quantitative detection of PARP activity and γH2AX foci in peripheral blood mononuclear cells (PBMCs) and tumor samples. Methods: PBMCs and tumor biopsies (optional) were collected, and validated assays were used to compare pre- and post-treatment levels of γH2AX and PAR, a product of PARP. PAR was measured by ELISA and γH2AX by immunofluorescence assay. Results: We enrolled 24 patients (pts) with refractory solid tumors and lymphomas. The dose of topotecan was reduced and administration schedule changed due to myelosuppression (Table). PARP was modulated by the various administration schedules. In PBMCs, >50% reduction in PAR was observed in 13 of 18 pts. When ABT-888 was given on D1 only, PAR levels in PBMCs returned to baseline levels by D2 in 3 of 5 pts. In the 3 pts for whom paired tumor biopsies were available, PAR reduction was 89.3% (pt on dose level [DL] 1), 98.7% (pt on DL-2), and 75.5% (pt on DL-3). Topotecan did not appear to alter the ability of ABT-888 to inhibit PARP. Elevated levels of γH2AX were detected in PBMCs after doses of 0.9 and 1.2 mg/m2/day topotecan alone but not lower doses. However, when given with ABT-888, 3 of 7 pts on DL-3 and all 3 pts on DL-2 had significant increases in γH2AX. γH2AX upregulation was associated with PARP inhibition; mean PAR reduction ± SD in PBMCs 2 h post-dose in pts on DL −3 was 97.8% ± 5.5% for γH2AX responders vs. 52.3% ± 28.1% for nonresponders. Conclusions: The PARP inhibitor ABT-888 potentiated DNA damage caused by topotecan as indicated by the increase in γH2AX foci. Funded by NCI Contract HHSN261200800001E. Dose and days (D) of administration Dose level Topotecan IV (mg/m2/day) ABT-888 (10 mg q12h PO) No. of patients 1 1.2 (D-8, 2-5) D1-7 6 −1 0.9 (D-8, 2-5) D1-7 3 −2 0.75 (D1-5) D2-5 3 −3 0.6 (D1-5) D2-5 7 1A 0.75 (D1-5) D1 only 5 No significant financial relationships to disclose.