Durairaj Chandrasekar, Ruiz-Garcia Ana, Gauthier Eric R, Huang Xin, Lu Dongrui R, Hoffman Justin T, Finn Richard S, Joy Anil A, Ettl Johannes, Rugo Hope S, Zheng Jenny, Wilner Keith D, Wang Diane D
Global Product Development, Pfizer Inc., San Diego.
Pfizer Inc.
Anticancer Drugs. 2018 Mar;29(3):271-280. doi: 10.1097/CAD.0000000000000589.
The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
本研究的目的是评估哌柏西利联合来曲唑对QTc的潜在影响。PALOMA-2是一项3期、随机、双盲、安慰剂对照试验，比较了哌柏西利加来曲唑与安慰剂加来曲唑在雌激素受体阳性、人表皮生长因子受体2阴性的绝经后晚期乳腺癌女性中的疗效。该研究包括一项QTc评估子研究，作为对哌柏西利明确的QT间期延长评估。在基线（第0天）和第1周期第14天的0、2、4、6和8小时进行时间匹配的三份心电图检查。从所有患者收集额外的心电图用于安全监测。使用弗里德里西亚校正法（QTcF）、巴泽特校正法（QTcB）和研究特定校正因子（QTcS）对心率进行QT间期校正。总共666例患者按2∶1随机分组接受哌柏西利加来曲唑或安慰剂加来曲唑治疗。其中，125例患者纳入QTc评估子研究。子研究中接受哌柏西利加来曲唑治疗组（N = 77）的患者，其基线后最大QTcS或QTcF值均未≥480毫秒，或QTcS或QTcF值较时间匹配的基线最大增加未≥60毫秒。在重复给予125毫克哌柏西利后，所有时间点以及稳态Cmax时，QTcS、QTcF和QTcB相对于时间匹配基线的平均变化的单侧95%置信区间上限均小于10毫秒。在推荐的治疗给药方案下，哌柏西利与来曲唑联合使用时，不会将QT间期延长至临床相关程度。
