BACKGROUND: Ixazomib is the first oral, proteasome inhibitor to reach phase III 
trials. Here, we present an integrated nonclinical and clinical assessment of 
ixazomib's effect on QTc intervals.
METHODS: Nonclinical studies assessed (1) the in vitro binding of ixazomib to 
the hERG channel and (2) its effect on QT/QTc in dogs (N = 4) via telemetry. 
Pharmacokinetic-matched triplicate electrocardiograms were collected in four 
clinical phase I studies of intravenous (0.125-3.11 mg/m(2), N = 125, solid 
tumors/lymphoma) or oral (0.24-3.95 mg/m(2), N = 120, multiple myeloma) 
ixazomib. The relationship between ixazomib plasma concentration and heart rate 
(HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was 
analyzed using linear mixed-effects models with fixed effects for day and time.
RESULTS: In vitro binding potency for ixazomib to the hERG channel was weak (K i 
24.9 μM; IC50 59.6 μM), and nonclinical telemetry studies showed no QT/QTc 
prolongation at doses up to 4.2 mg/m(2). In cancer patients, ixazomib, when 
evaluated at doses yielding various plasma concentrations (with 26 % of data 
greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on 
QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was 
no relationship between ixazomib concentration and RR, suggesting no effect on 
HR.
CONCLUSIONS: Ixazomib has no clinically meaningful effects on QTc or HR. 
Integrating preclinical data and concentration-QTc modeling of phase 1 data may 
obviate the need for a dedicated QTc study in oncology. A framework for QT 
assessment in oncology drug development is proposed.