Kathleen Moore1,2, John K Chan3, Angeles Alvarez Secord4, Manish R Patel5,6, Timothy Callahan7, Wei Guo8, Zhi-Yi Zhang8. 1. Stephenson Cancer Center, University of Oklahoma HSC, 800 NE 10th St #2500, Oklahoma City, OK, 73104, USA. Kathleen-Moore@ouhsc.edu. 2. Sarah Cannon Research Institute, Nashville, TN, USA. Kathleen-Moore@ouhsc.edu. 3. Palo Alto Medical Foundation, California Pacific Medical Center, Sutter Health Sutter West Bay, San Francisco, CA, USA. 4. Duke Cancer Institute, Durham, NC, USA. 5. Sarah Cannon Research Institute, Nashville, TN, USA. 6. Florida Cancer Specialists and Research Institute, Sarasota, FL, USA. 7. BioTel Research, Rockville, MD, USA. 8. TESARO, Inc, Waltham, MA, USA.
Abstract
PURPOSE: Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia's formula (ΔQTcF) and niraparib plasma concentrations. METHODS:Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity. RESULTS: Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: - 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib. CONCLUSION:Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.
RCT Entities:
PURPOSE: Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia's formula (ΔQTcF) and niraparib plasma concentrations. METHODS:Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity. RESULTS: Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: - 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib. CONCLUSION:Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.
Authors: Gottfried E Konecny; Amit M Oza; Anna V Tinker; Ana Oaknin; Ronnie Shapira-Frommer; Isabelle Ray-Coquard; Carol Aghajanian; Robert L Coleman; David M O'Malley; Alexandra Leary; Lee-May Chen; Diane Provencher; Ling Ma; James D Brenton; Cesar Castro; Michelle Green; Andrew D Simmons; Jeri Beltman; Thomas Harding; Kevin K Lin; Sandra Goble; Lara Maloney; Rebecca S Kristeleit; Iain A McNeish; Elizabeth M Swisher; Jim J Xiao Journal: Gynecol Oncol Date: 2021-03-19 Impact factor: 5.304