Integrated Nonclinical And Clinical Risk Assessment To Obviate The Need For A Dedicated Qtc Study Of Ixazomib Citrate (Mln9708) In Cancer Patients (Pts)

2553 Background: Ixazomib citrate is an investigational oral proteasome inhibitor in phase 3 (P3) clinical development. It is expected to have a favorable cardiac safety profile based on weak in vitro inhibition of the hERG channel (IC50 59.6 μM) and in vivo nonclinical data. To confirm, serial PK-matched triplicate electrocardiograms (ECGs) were collected in phase 1 (P1) dose-escalation studies to characterize the effect of the active moiety ixazomib (Ix; MLN2238) on QTc intervals and potentially obviate the need for a dedicated QTc study. Methods: Data from 245 pts in 2 IV (0.125–3.11 mg/m2, N=125, solid tumor and lymphoma pts) and 2 oral (0.24–3.95 mg/m2, N=120, multiple myeloma pts) P1 studies were included. Mean (range) age was 56.5 (23–86) years; 43% were female. Centrally read 12-lead digital ECGs were used to derive heart rate (HR)-corrected QT intervals using Fridericia’s method (QTcF). Relationship between Ix plasma concentration (C) and QTcF was analyzed using linear mixed effects models with f...