1. Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy
- Author
-
Hartmut Goldschmidt, Christoph Heuck, Markus Munder, Edward N. Libby, Maria Teresa Petrucci, Mehmet Turgut, Michele Cavo, Tobias Neff, Ming Qi, Katja Weisel, Robert Kleiman, Mario Boccadoro, Fatih Demirkan, Steven Kuppens, Ihsan Karadogan, Ajai Chari, Pamela L. Clemens, Rajesh Bandekar, Ceri Bygrave, Matthew W Jenner, Niels W.C.J. van de Donk, Chari A., Munder M., Weisel K., Jenner M., Bygrave C., Petrucci M.T., Boccadoro M., Cavo M., van de Donk N.W.C.J., Turgut M., Demirkan F., Karadogan I., Libby E., Kleiman R., Kuppens S., Bandekar R., Neff T., Heuck C., Qi M., Clemens P.L., and Goldschmidt H.
- Subjects
Monoclonal antibody ,Cardiac function curve ,medicine.medical_specialty ,Phases of clinical research ,QT interval ,Pharmacokinetic-pharmacodynamic analysis ,Electrocardiography ,QRS complex ,Heart Rate ,Daratumumab ,Internal medicine ,Heart rate ,medicine ,Humans ,Pharmacology (medical) ,cardiovascular diseases ,Smoldering multiple myeloma ,Multiple myeloma ,Original Research ,Pharmacokinetic-pharmacodynamic analysi ,business.industry ,Antibodies, Monoclonal ,General Medicine ,medicine.disease ,Confidence interval ,Cardiology ,business ,QTc substudy - Abstract
Introduction Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling. Methods Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia’s formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted. Results Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5–12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF. Conclusion Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab. Trial Registration ClinicalTrials.gov Identifier: NCT02316106. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01601-w.
- Published
- 2021