Abstract
Purpose
To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of motesanib. The framework was evaluated using results from a phase 2 study of motesanib in thyroid cancer.
Methods
Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with differentiated thyroid cancer and 91 patients with medullary thyroid cancer, who received motesanib 125 mg once daily. The models, combined with previously developed population pharmacokinetic and tumor growth inhibition models, were assessed in predicting dose intensity, tumor size over time, objective response rate, and progression-free survival. Dose–response simulations were performed in patients with differentiated thyroid cancer.
Results
The predicted objective response rate and median progression-free survival in patients with differentiated thyroid cancer was 15.0% (95% prediction interval, 7.5%–23.7%) and 40 weeks (95% prediction interval, 32–49 weeks), respectively, compared with the observed objective response rate of 14.0% and median progression-free survival of 40 weeks. The simulated median objective response rate increased with motesanib starting dose from 13.5% at 100 mg once daily to 38.0% at 250 mg once daily. However, simulated median progression-free survival was independent of starting dose, ranging from 40.5 weeks (95% prediction interval, 38.6–46.9 weeks) at 100 mg once daily to 40.0 weeks (95% prediction interval, 38.6–46.8 weeks) at 250 mg once daily.
Conclusions
Dose–response simulations confirmed the appropriateness of 125-mg once-daily dosing; no clinically relevant improvement in progression-free survival would be obtained by dose intensification. This modeling framework represents an important tool to simulate clinical response and support clinical development decisions.
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Acknowledgments
The authors wish to thank Benjamin Scott, PhD (Complete Healthcare Communications, Inc., Chadds Ford, PA), whose work was funded by Amgen Inc., for editorial assistance in the preparation of this manuscript.
Conflict of interest
LC and RB are employees of Pharsight and contractors to Amgen Inc. J-FL, and Y-NS are employees of and stockholders in Amgen Inc.
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L. Claret and J.-F. Lu contributed equally to this manuscript.
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Claret, L., Lu, JF., Sun, YN. et al. Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer. Cancer Chemother Pharmacol 66, 1141–1149 (2010). https://doi.org/10.1007/s00280-010-1449-z
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DOI: https://doi.org/10.1007/s00280-010-1449-z