Abstract
Purpose
This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens.
Methods
Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens.
Results
The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400–2000 mg q2w in combination regimens were consistent with the model predictions.
Conclusion
PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.
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Acknowledgements
The authors would like to thank the entire BP27771 study team at Penzberg for their assistance in the preparation of this manuscript. Support for third-party writing assistance for this article, furnished by Jamie Ashman, PhD, was provided by Prism Ideas and funded by Roche Diagnostics GmbH, Penzberg.
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This study was funded by Roche Diagnostics GmbH, Penzberg, Germany.
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All authors are employees of F. Hoffmann-La Roche Ltd.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Informed consent was obtained from all individual participants included in the study.
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Meneses-Lorente, G., McIntyre, C., Hsu, J.C. et al. Accelerating drug development by efficiently using emerging PK/PD data from an adaptable entry-into-human trial: example of lumretuzumab. Cancer Chemother Pharmacol 79, 1239–1247 (2017). https://doi.org/10.1007/s00280-017-3328-3
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DOI: https://doi.org/10.1007/s00280-017-3328-3