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Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies

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Abstract

Purpose

Brentuximab vedotin (ADCETRIS®), an antibody–drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization.

Methods

Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia’s corrected QT interval (QTcF).

Results

There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies.

Conclusion

There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

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Acknowledgments

Research funding for the study was provided by Seattle Genetics, Inc. and Millennium: The Takeda Oncology Company. The authors wish to acknowledge Nancy Whiting for protocol development; Elizabeth Thomas, Pamela Levine, Bess Sorensen, and Mike Thorn for statistical guidance; Dr. Tim Callahan for ECG interpretation; and Jennifer Houser for medical writing assistance, all under the sponsorship of Seattle Genetics, Inc. The authors would also like to express their gratitude to patients and their families.

Conflict of interest

None.

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Authors and Affiliations

  1. Seattle Genetics, Inc., 21823, 30th Drive Southeast, Bothell, WA, 98021, USA

    T. H. Han & N. N. Hunder

  2. City of Hope National Medical Center, Duarte, CA, USA

    R. Chen

  3. Stanford University Medical Center, Stanford, CA, USA

    R. Advani

  4. Baylor University Medical Center, Dallas, TX, USA

    R. B. Berryman

  5. Loyola University Medical Center, Maywood, IL, USA

    S. E. Smith

  6. University of Alabama at Birmingham, Birmingham, AL, USA

    A. Forero-Torres

  7. University of Miami Miller School of Medicine, Miami, FL, USA

    J. D. Rosenblatt

  8. Cleveland Clinic, Cleveland, OH, USA

    M. R. Smith

  9. Fox Chase Cancer Center, Philadelphia, PA, USA

    M. R. Smith

  10. Columbia University Medical Center, New York, NY, USA

    J. Zain

  11. New York University Cancer Institute, New York, NY, USA

    J. Zain

  12. University Hospital of Cologne, Cologne, Germany

    A. Engert

Authors
  1. T. H. Han
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  2. R. Chen
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  3. R. Advani
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  4. R. B. Berryman
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  5. S. E. Smith
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  6. A. Forero-Torres
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  7. J. D. Rosenblatt
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  8. M. R. Smith
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  9. J. Zain
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  10. N. N. Hunder
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  11. A. Engert
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Corresponding author

Correspondence to T. H. Han.

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Han, T.H., Chen, R., Advani, R. et al. Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies. Cancer Chemother Pharmacol 72, 241–249 (2013). https://doi.org/10.1007/s00280-013-2192-z

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  • DOI: https://doi.org/10.1007/s00280-013-2192-z

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