title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: 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, SThomas@mdanderson.org.
authors.forename: Sheeba K
authors.initials: SK
authors.lastname: Thomas
authors.forename: Alexander
authors.initials: A
authors.lastname: Suvorov
authors.forename: Lucien
authors.initials: L
authors.lastname: Noens
authors.forename: Oleg
authors.initials: O
authors.lastname: Rukavitsin
authors.forename: Joseph
authors.initials: J
authors.lastname: Fay
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Wu
authors.forename: Todd M
authors.initials: TM
authors.lastname: Zimmerman
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bandekar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Clarissa
authors.initials: C
authors.lastname: Uhlar
authors.forename: Olga S
authors.initials: OS
authors.lastname: Samoylova
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000188:drug therapy*; D009101:Multiple Myeloma / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; C504234:siltuximab