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.
キーワード
概要
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.
