Shruti Agrawal1, Ian Waxman2, Alexandre Lambert3, Amit Roy2, Raymond Darbenzio2. 1. Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA. shruti.agrawal@bms.com. 2. Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA. 3. Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
Abstract
PURPOSE: The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab. METHODS: Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia's formula (QTcF) was evaluated by central tendency, categorical, and concentration-response analyses. RESULTS: No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (± SD) ∆QTcF at any time point were 4.9 (± 13.4), 1.2 (± 10.1), and 2.0 (± 8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group. CONCLUSION: Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.
RCT Entities:
PURPOSE: The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab. METHODS: Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia's formula (QTcF) was evaluated by central tendency, categorical, and concentration-response analyses. RESULTS: No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (± SD) ∆QTcF at any time point were 4.9 (± 13.4), 1.2 (± 10.1), and 2.0 (± 8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group. CONCLUSION: Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.
Authors: David Pérez-Callejo; María Torrente; María Auxiliadora Brenes; Beatriz Núñez; Mariano Provencio Journal: Med Oncol Date: 2017-08-09 Impact factor: 3.064
Authors: Abdulrazzak Zarifa; Juan Lopez-Mattei; Nicolas L Palaskas; Cezar Iliescu; Jean-Bernard Durand; Peter Y Kim Journal: Adv Exp Med Biol Date: 2021 Impact factor: 2.622
Authors: Chandrasekar Durairaj; Ana Ruiz-Garcia; Eric R Gauthier; Xin Huang; Dongrui R Lu; Justin T Hoffman; Richard S Finn; Anil A Joy; Johannes Ettl; Hope S Rugo; Jenny Zheng; Keith D Wilner; Diane D Wang Journal: Anticancer Drugs Date: 2018-03 Impact factor: 2.248