The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) and after (0-15 and 60-75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia’s correction was applied to QT measurements (QTcF) and change from baseline (Δ QTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure-response relationships between Δ QTcF and observed pertuzumab concentrations. Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔ QTcF (90 % CI) values at 0-15 min, 60-75 min, and 72 h post-infusion were -6.96 (-13.69, -0.23), -6.35 (-13.57, 0.88), and -4.08 (-12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ΔΔQTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration-QTc modeling showed no apparent relationship between Δ QTcF and pertuzumab concentrations. Cardiac monitoring and concentration-QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters.
2013 年 09 月 3 日
Author(s): Amit Garg, Jing Li, Emma Clark, Adam Knott, Timothy Carrothers, Jean-Francois Marier, Javier Cortés, Michael Brewster, Jennifer Visich, Bert Lum
Year: 2013 年 09 月 3 日