Abstract P3-14-07: Evaluation of the effects of talazoparib on QT interval prolongation
Authors: Hoffman J , Chakrabarti J , Wainberg ZA , Plotka A , Babu S , Milillo Naraine A , Kanamori D , Moroose R , Nguyen L , Wang D 
Published: May 2019

Abstract
Background: Talazoparib (TAL), an oral poly ADP-ribose polymerase inhibitor, is under investigation in multiple oncologic clinical trials and has been submitted to the US FDA for use in patients (pts) with germline BRCA-mutated, HER2-negative advanced breast cancer.
International Conference on Harmonisation guidance recommends all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in pts is required in the registration dossier. The effect of steady-state (ss) TAL (1 mg once daily) on cardiac repolarization in pts with advanced solid tumors was evaluated in an open-label phase 1 study (NCT03042910).
Methods: Continuous 12-lead electrocardiogram (ECG) recordings were collected at baseline (Day -1); time-matched pharmacokinetic (PK) samples and continuous ECG recordings were obtained on Days 1, 2, and 22 (when TAL concentrations achieved ss). On Day -1, pts had continuous 12-lead ECG recording starting at Time 0 (Day 1 dosing time) for 6 hrs. On Days 1 and 22, ECG recording started 45 min before TAL administration and continued for 6 hrs post dose and blood samples for PK were collected before dose and at 1, 2, 4, and 6 hrs post dose. On Day 2, a 30-min ECG recording and a PK sample were obtained before dose at Time 0.
Continuous ECG recordings were submitted to a central laboratory; triplicate 10-sec ECGs were extracted from a 5-min extraction window beginning 15 min before each PK collection time. ECG measurements were reported via blinded manual adjudication process and included PR interval, QT interval, RR interval, and QRS complex. The QT interval was corrected for effect of heart rate using Fridericia's correction (QTcF) and Bazett's correction (QTcB).
The estimate of change from time-matched baseline and its 2-sided 90% confidence interval (CI) was calculated for each nominal time point using PROC MEANS. Additionally, a prespecified PK/pharmacodynamic (PD) model was used to describe the relationship between plasma TAL concentrations ([TAL]) and QTc. The prespecified linear mixed-effects model included [TAL], time (categorical), and treatment with random pt effects on [TAL] and the intercept. If the upper bounds (UB) of 1-sided 95% CIs of time-matched ΔQTc for all ECG time points were &lt;20 msec and the UB of 1-sided 95% CIs of the predicted ΔQTc at the mean ss maximum [TAL] was &lt;20 msec, the effect of TAL on QTc was not of clinical relevance.
Results: 37 of 38 pts enrolled received TAL and were included in the ECG and PK/PD analyses. No pts had a postbaseline absolute maximum QTcF or QTcB ≥500 msec or ΔQTc ≥60 msec. The UB of the 1-sided 95% CI for the time-matched ΔQTcF and ΔQTcB were &lt;12 msec at all nominal ECG time points. In the PK/PD analysis, the slopes (95% CI) of QTcF-[TAL] and QTcB-[TAL] relationships were -0.14 (-0.78 to 0.50) msec/ng/mL and -0.24 (-0.88 to 0.41) msec/ng/mL, respectively, indicating that TAL did not have a concentration-dependent effect on QTcF or QTcB.
Conclusion: TAL does not have a clinically relevant effect on QTc.
Funding: Medivation LLC, acquired by Pfizer.
Citation Format: Hoffman J, Chakrabarti J, Wainberg ZA, Plotka A, Babu S, Milillo Naraine A, Kanamori D, Moroose R, Nguyen L, Wang D. Evaluation of the effects of talazoparib on QT interval prolongation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-07.