Abstract P4-22-10: Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc
Authors: Ruiz A , Gauthier E , Durairaj C , Huang X , Hoffman J , Finn RS , Moulder S , Joy AA , Ettl J , Rugo HS , Wang D 
Published: March 2017

Abstract
Background: PAL , an oral cyclin dependent kinase (CDK) 4/6 inhibitor, is under investigation in multiple oncologic clinical trials and is currently approved for use in multiple countries in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC).
International Conference on Harmonization guidance recommends that 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 non-adjuvant anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in patients [pts] is required in the registration dossier. The phase 3 PALOMA-2 study (N=666) confirmed the superior clinical benefit of PAL+LET vs placebo (P) + LET in postmenopausal women with estrogen receptor positive/HER2– ABC who have not received any prior systemic anticancer therapies for ABC. One of the secondary objectives of the study was to evaluate the effects of PAL+LET on QTc.
Methods: 12 lead (with a 10 second rhythm strip) tracings were performed in triplicate ∼2 min apart but within 10 min for all 3 ECGs. On the day preceding the initiation of treatment (Day 0), triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hrs (baseline). On Cycle 1 Day 14, when PAL concentrations were at steady-state, triplicate ECGs time-matched to baseline ECGs collected on Day 0 (±35 min) were obtained following PAL or P dosing. All ECGs were sent to a central laboratory for blinded manual adjudication and these data were used for analysis. ECG measurements included PR interval, QT interval, RR interval and QRS complex. The QT interval was corrected for the effect of heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS).
Approximately 60 pts were to be included for QTc evaluation to ensure 40 evaluable pts in the PAL+LET arm (2:1 randomization) of PALOMA-2 and thus, to establish noninferiority between post-baseline and baseline (ΔQTc) at all 5 QTc sampling timepoints on Cycle 1 Day 14 with 90% power. The test was based on a 1-sided difference in means t test for paired ΔQTc (α= 0.05). The difference in means between ΔQTc under the alternative hypothesis is 10 ms, assuming a noninferiority margin of 20 ms and the standard deviation of the paired differences equal to 16 ms based on PALOMA-1 study. If the upper bounds (UB) of 1-sided 95% confidence intervals (CI) of ΔQTc for all 5 QTc time points were &lt;20 ms, the post-baseline QTc will be considered noninferior to baseline and PAL+LET effect on QTc will be concluded to be not of clinical relevance.
Results: A total of 77 pts were enrolled for intensive QTc assessment in PAL+LET arm. No pts had a post-baseline absolute maximum QTcF, QTcS or QTcB ≥500 ms or a ΔQTc ≥60 ms during the intensive QTc assessment period. A random effect analysis of the mean ΔQTc data demonstrated that the UB of the 1-sided 95% CI for QTcF, QTcS, and QTcB were &lt;8 ms at all 5 QTc sampling time points.
Conclusion: PAL+LET does not have a clinically relevant effect on QTc.
Sponsor: Pfizer
Citation Format: Ruiz A, Gauthier E, Durairaj C, Huang X, Hoffman J, Finn RS, Moulder S, Joy AA, Ettl J, Rugo HS, Wang D. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-10.