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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• 作者：Sheeba K. Thomas (1)
  Alexander Suvorov (2)
  Lucien Noens (3)
  Oleg Rukavitsin (4)
  Joseph Fay (5)
  Ka Lung Wu (6)
  Todd M. Zimmerman (7)
  Helgi van de Velde (8)
  Rajesh Bandekar (9)
  Thomas A. Puchalski (10)
  Ming Qi (11)
  Clarissa Uhlar (11)
  Olga S. Samoylova (12)
  
• 关键词：Smoldering multiple myeloma ; Siltuximab ; Interleukin ; 6 ; QT interval ; Cardiac repolarization ; Monoclonal gammopathy of undetermined significance
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：73
• 期：1
• 页码：35-42
• 全文大小：301 KB
• 作者单位：Sheeba K. Thomas (1)
  Alexander Suvorov (2)
  Lucien Noens (3)
  Oleg Rukavitsin (4)
  Joseph Fay (5)
  Ka Lung Wu (6)
  Todd M. Zimmerman (7)
  Helgi van de Velde (8)
  Rajesh Bandekar (9)
  Thomas A. Puchalski (10)
  Ming Qi (11)
  Clarissa Uhlar (11)
  Olga S. Samoylova (12)
  
  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
  2. Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia
  3. Department of Hematology, Ghent University Hospital, Ghent, Belgium
  4. Haematological Centre, Burdenko Main Military Clinical Hospital, Moscow, Russia
  5. Baylor Research Institute and Sammons Cancer Center, Baylor University, Dallas, TX, USA
  6. Department of Hematology, ZNA Stuivenberg, Antwerp, Belgium
  7. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA
  8. Oncology Development, Janssen Research and Development, LLC, Beerse, Belgium
  9. Biostatistics Oncology, Janssen Research and Development, LLC, Spring House, PA, USA
  10. Biologics Clinical Pharmacology, Biotechnology Center of Excellence, Janssen Research and Development, LLC, Spring House, PA, USA
  11. Clinical Oncology, Janssen Research and Development, LLC, Spring House, PA, USA
  12. Hematological Department, Regional Clinical Hospital N.A Semashko, Nizhni Novgorod, Russia
  
• ISSN：1432-0843

文摘

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?≤?00?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 ?.01, 6.45] ms; QTcB?=?2.7 [?.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was ?.5?ms and upper bound 90?% CI was ?.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.