Concentration–QTc Analysis of Valemetostat in Patients With Hematologic Malignancies

This study assessed the potential risk of QT prolongation associated with the dual enhancer of zeste homolog 1/2 inhibitor valemetostat. An evaluation of the relationship between plasma valemetostat concentration and heart‐rate‐corrected QT (QTc) interval was performed. Time‐matched plasma concentration and 12‐lead electrocardiogram data were collected from the phase I studies DS3201‐A‐J101, in patients with relapsed/refractory B‐/T‐cell non‐Hodgkin lymphomas (NCT02732275), and DS3201‐A‐U102, in patients with relapsed/refractory acute myeloid leukemia and acute lymphoblastic leukemia (NCT03110354). A prespecified linear mixed‐effects model was used to assess the effect of valemetostat on change in QTc corrected by the Fridericia method (ΔQTcF). A population‐specific method (ΔQTcP) was also used to remove the heart rate interval (RR) dependence. The final dataset contained 769 electrocardiogram measurements from 100 patients. Linear mixed‐effects modeling found no significant demographic or clinical covariate effects. The slope versus concentration was significant (95% confidence interval [CI] of the coefficient excluded 0) in the final models for ΔQTcF, but not ΔQTcP, while the relative standard error of the slope was > 50% for both models. Baseline QTc had a negative effect on ΔQTc in all models. At the steady‐state geometric mean maximum concentrations in the dose range of 100–700 mg tested in the DS3201‐A‐J101 and DS3201‐A‐U102 studies, the 90% CI upper bounds for model‐predicted ΔQTcF and ΔQTcP were 1.52–8.38 ms, all of which were below the clinically significant threshold of 10 ms. The analysis supports a lack of a clinically meaningful effect on the QTc interval for valemetostat.