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Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma

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Abstract

Purpose

A phase 1 study evaluated the QTc prolongation potential of siltuximab, a chimeric, anti-interleukin-6 mAb, in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or low-volume MM.

Methods

Patients with baseline QTcF and QTcB ≤ 500 ms, QRS < 100 ms, PR < 200 ms and no significant cardiac disease received siltuximab 15 mg/kg q3w, the highest dosage used in clinical studies, for 4 cycles. Twelve-lead ECGs obtained at multiple time points pre- and post-infusion at cycles 1 and 4 were evaluated by central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of least square (LS) mean 90 % CI for QTc change from baseline at each time point was <20 ms.

Results

An effect on QTc prolongation was ruled out, as the upper bound of 90 % CI was <10 ms at each time point in 27 evaluable patients (13 MGUS, 13 SMM, 1 low-volume MM) with no differences between disease types. Maximum mean QTc increase from baseline occurred 3 h after cycle 1 infusion (QTcF = 3.2 [LS mean 90 % CI −0.01, 6.45] ms; QTcB = 2.7 [−0.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was ≤1.5 ms and upper bound 90 % CI was ≤5.1 ms. Twenty patients had mostly low-grade AEs, including nausea, fatigue (20 % each); thrombocytopenia, headache (each 13 %); dyspnea, leukopenia, neutropenia, paresthesia, abnormal hepatic function, URTI (each 10 %). Three MGUS patients achieved 50 % M-protein reduction. There was no association between siltuximab pharmacokinetics and QTc interval.

Conclusions

Siltuximab did not affect the QTc interval. Overall safety was similar to other single-agent siltuximab studies.

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Acknowledgments

The authors thank Jennifer Han of Janssen Services, LLC, for providing medical writing support in developing and preparing this manuscript for publication.

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Authors and Affiliations

  1. Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0429, Houston, TX, 77030, USA

    Sheeba K. Thomas

  2. Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia

    Alexander Suvorov

  3. Department of Hematology, Ghent University Hospital, Ghent, Belgium

    Lucien Noens

  4. Haematological Centre, Burdenko Main Military Clinical Hospital, Moscow, Russia

    Oleg Rukavitsin

  5. Baylor Research Institute and Sammons Cancer Center, Baylor University, Dallas, TX, USA

    Joseph Fay

  6. Department of Hematology, ZNA Stuivenberg, Antwerp, Belgium

    Ka Lung Wu

  7. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    Todd M. Zimmerman

  8. Oncology Development, Janssen Research and Development, LLC, Beerse, Belgium

    Helgi van de Velde

  9. Biostatistics Oncology, Janssen Research and Development, LLC, Spring House, PA, USA

    Rajesh Bandekar

  10. Biologics Clinical Pharmacology, Biotechnology Center of Excellence, Janssen Research and Development, LLC, Spring House, PA, USA

    Thomas A. Puchalski

  11. Clinical Oncology, Janssen Research and Development, LLC, Spring House, PA, USA

    Ming Qi & Clarissa Uhlar

  12. Hematological Department, Regional Clinical Hospital N.A Semashko, Nizhni Novgorod, Russia

    Olga S. Samoylova

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  1. Sheeba K. Thomas
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Correspondence to Sheeba K. Thomas.

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Thomas, S.K., Suvorov, A., Noens, L. et al. Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma. Cancer Chemother Pharmacol 73, 35–42 (2014). https://doi.org/10.1007/s00280-013-2314-7

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  • DOI: https://doi.org/10.1007/s00280-013-2314-7

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