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Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes

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Abstract

Purpose

This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC).

Methods

Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration.

Results

Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10–15 ms increase in delta–delta Fridericia corrected QT (∆∆QTcF) and delta–delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study.

Conclusions

Cabozantinib treatment prolongs the ∆∆QTcF interval by 10–15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

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Authors and Affiliations

  1. Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA

    Dale R. Miles, Steven A. Lacy, Steve Milwee, Yifah Yaron & Linh T. Nguyen

  2. Quantitative Solutions, LP 845 Oak Grove #115, Menlo Park, CA, 94025, USA

    David R. Wada

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  1. Dale R. Miles
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  2. Steven A. Lacy
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  3. David R. Wada
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  4. Steve Milwee
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  6. Linh T. Nguyen
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Corresponding author

Correspondence to Steven A. Lacy.

Ethics declarations

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. Informed consent was obtained from all individual participants included in the study.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Conflict of interest and source of funding

These analyses were funded by Exelixis, Inc. Steve Lacy and Steve Milwee are full-time employees and stockholders of Exelixis Inc. Dale Miles, Yifah Yaron, and Linh Nguyen were full-time employees and stockholders of Exelixis, Inc. when the work was performed. Dale Miles is currently employed Genentech Inc. and Linh Nguyen is currently employed by Pfizer Inc. David Russ Wada is a full-time employee of Certara, which was contracted to perform some analyses.

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Miles, D.R., Lacy, S.A., Wada, D.R. et al. Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes. Cancer Chemother Pharmacol 80, 295–306 (2017). https://doi.org/10.1007/s00280-017-3349-y

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