Abstract
Purpose
The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer.
Methods
Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1–4 and at the SDDV. Fridericia’s correction was applied to QT recordings (QTcF), and change from baseline (ΔQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (ΔΔQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration–ΔQTcF relationship.
Results
Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar ΔQTcF and ΔΔQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration–ΔQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 μg/ml.
Conclusions
These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval.
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Acknowledgments
The authors would like to acknowledge the contribution of Melinda Teng in developing an analysis plan and reviewing the ECG analyses. Support for third-party writing assistance for this manuscript was provided by Genentech, Inc.
Conflict of interest
The study was funded by F. Hoffmann-La Roche Ltd., Basel, Switzerland, and Genentech, Inc., a member of the Roche Group, South San Francisco, CA, USA. MTB was a paid consultant of Genentech, Inc. for this project. MC is an employee of F. Hoffmann-La Roche Ltd. SM, WA, SP, and MS are Genentech employees and own Roche stock. IR and JC are Pharsight employees.
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Borin, M.T., Chen, M., Mocci, S. et al. Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer. Cancer Chemother Pharmacol 75, 401–410 (2015). https://doi.org/10.1007/s00280-014-2652-0
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DOI: https://doi.org/10.1007/s00280-014-2652-0