Abstract A220: Inhibition of PBMC PARP activity with the novel PARP 1/2 inhibitor BMN 673 in patients with advanced solid tumors.

Abstract

Abstract Introduction: BMN 673 is a novel, potent (IC50 < 1.0 nM) inhibitor of Poly(ADP-ribose) polymerase (PARP) 1 and PARP 2 in clinical development for the treatment of genetically defined cancers. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of BMN 673 were evaluated in a Phase 1 dose-escalation study in patients with advanced solid tumors. Oral doses evaluated ranged from 0.025 to 1.1 mg/day, with 3-6 patients evaluated at each dose level in a standard 3+3 design. The first dose in Cycle 1 was followed for 7 days without dosing for collection of serial PK and PD samples. Thereafter BMN 673 was administered once daily on Days 8 to 35, with predose PK and PD samples collected on Days 15 and 22. Following the last dose in Cycle 1 on Day 35, serial PK and PD samples were collected for 7 and 3 days, respectively, without dosing. In subsequent cycles, BMN 673 was administered daily in contiguous 28-day cycles. The PD activity of BMN 673 was measured in peripheral blood mononuclear cells (PBMCs) using assay methods previously described (Clin Cancer Res 2008 14:7917023, Biochem J 2011 436:671-679). Correlations between systemic BMN 673 exposure and inhibition of PBMC PARP activity were investigated across dose levels. Results: BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). While variable across and within patients, overall PBMC PARP activity decreased in a dose-dependent manner. Within individual patients at higher dose levels, PBMC PARP activity decreased soon after the first dose of BMN 673, and activity remained at suppressed levels with daily dosing. PBMC PARP activity rebounded when dosing was stopped, indicating the return of PARP function. Correlations between the mean percent baseline PARP activity with daily BMN 673 dosing and measures of steady-state BMN 673 exposures within individuals (i.e., Day 35 Cmin, Cmax, and AUC0-24) showed decreased PARP activity with increasing exposure. This correlation was well described using an Imax model with IC50 values based on an interim analyses of 1140 pg/mL, 3090 pg/mL, and 26700 pg-hr/mL for Cmin, Cmax, and AUC0-24, respectively. Conclusions: PBMC PARP activity was rapidly and continuously inhibited with daily dosing of BMN 673. A positive correlation between systemic BMN 673 exposure and inhibition of PARP activity in PBMCs was demonstrated. This effect on a relevant pharmacodynamic marker provides in vivo proof of an on-target effect of BMN 673 and may be an initial step with potential to inform BMN 673 dose selection. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A220. Citation Format: Joshua W. Henshaw, Huiyu Zhou, Ashleigh Herriott, Miranda Patterson, Evelyn W. Wang, Don Musson, Johann de Bono, Lida A. Mina, Ramesh K. Ramanathan, Charles O'Neill, Andrew Dorr, Nicola J. Curtin. Inhibition of PBMC PARP activity with the novel PARP 1/2 inhibitor BMN 673 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A220.