Abstract CT149: Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study
Authors: Munasinghe Wijith , Tolcher Anthony , Calvo Emiliano , Gordon Michael , Jalving Mathilde , de Vos-Geelen Judith , Medina Diane M. , Bergau Dennis M. , Nuthalapati Silpa , Hoffman David M. , Shepherd Stacie L. , Xiong Hao 
Published: July 2016

Abstract
Veliparib is a potent oral poly(ADP-ribose) polymerase inhibitor that impairs DNA damage repair and shows single-agent activity in tumors with homologous recombination repair defects as well as in combination with DNA-damaging chemotherapies. Nonclinical studies suggested a potential risk of QT prolongation at the peak plasma concentration (Cmax) achieved at the maximum tolerated dose for veliparib monotherapy (400 mg twice daily). This phase 1, single-dose, double-blind, placebo (PBO)-controlled, randomized crossover study (NCT02009631) evaluated the effect of veliparib on corrected QT (QTc) interval in patients (pts) with relapsed/refractory solid tumors. Methods: Eligible pts (?18 years) with metastatic or unresectable solid tumors and ECOG PS ?1 received single-dose oral veliparib (200 mg [V200], 400 mg [V400]) or PBO in a 6-sequence, 3-period crossover design, with ?3-day interperiod washout time. The primary objective was to assess the effect of veliparib on QT interval with Fridericia's correction (QTcF). Lack of clinically relevant effect on QTc interval was shown if the 95% upper confidence bound (UCB) for the maximum baseline-adjusted QTcF difference between veliparib and PBO (??QTcF) for the 400 mg dosing was &lt;10 msec (ICH E14 guidelines). Pharmacokinetics and safety were also evaluated. Results: Forty-seven pts (85% female; median age 58 years) were enrolled and analyzed. After single-dose administration, maximum ??QTcF of V400 compared to PBO was 6.4 msec with a 95% UCB of 8.9 msec; for V200 the maximum ??QTcF was 3.6 msec, with a 95% UCB of 6.1 msec. Mean time to maximum plasma concentration (Tmax) was similar for V200 (2.4 ± 0.7 h) and V400 (2.5 ± 0.6 h). Mean Cmax was 1.32 ± 0.38 μg/mL and 2.61 ± 0.85 μg/mL, and total exposure (AUC?) was 12.0 ± 3.98 μg•h/mL and 25.5 ± 8.37 μg•h/mL, for V200 and V400, respectively. Treatment-emergent adverse events (TEAEs) were experienced by 36.2%, 48.9%, and 47.8% of pts while receiving V200, V400, and placebo, respectively. Most common TEAEs were nausea (12.8%) and myalgia (8.5%) while receiving V200; nausea (8.5%) and vomiting (8.5%) while receiving V400; and nausea (6.5%) while receiving PBO. TEAEs were mainly grade 1/2, with grade 3 vomiting and depression experienced by 1 pt each. The most common TEAE possibly related to study drug was nausea (19.1%), reported in 8.5%, 6.4%, and 4.3% of pts while receiving V200, V400, and PBO, respectively. One pt discontinued treatment after the V200-V400 sequence due to study drug-unrelated AEs. There were no deaths or serious AEs. Conclusions: Single-dose veliparib (200 or 400 mg) did not exhibit clinically relevant QT prolongation greater than the 10 msec threshold per ICH E14 guideline.
Citation Format: Wijith Munasinghe, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane M. Medina, Dennis M. Bergau, Silpa Nuthalapati, David M. Hoffman, Stacie L. Shepherd, Hao Xiong. Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT149.