Lessons learned: Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs.The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer.
Background: Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia's formula (QTcF) in patients with advanced cancer.
Methods: Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline.
Results: Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline.
Conclusion: Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF.
作者总结
经验
• 心脏毒性可能是抗肿瘤治疗的严重并发症之一。为能够早期鉴别药物相关心脏作用, 国际协调会议 （ICH） 采纳了 ICH E14 指南用于评价非抗心律失常药导致 QT/校正 QT （QTc） 间期延长的可能性和致心律失常的可能性。
• 本研究评价了雷莫芦单抗对 QT/QTc 间期的影响, 结果显示该药对晚期癌症患者的 QTc 延长没有影响。
摘要
背景. 雷莫芦单抗是人免疫球蛋白 G1 单克隆抗体, 可特异性地阻断血管内皮生长因子受体 2, 已获批准用于治疗晚期胃癌、非小细胞肺癌和结直肠癌。本项 II 期研究旨在确定雷莫芦单抗是否会导致晚期癌症患者校正 QT 间期延长, 校正 QT 间期使用 Fridericia 公式计算 （QTcF）。
方法. 患者接受雷莫芦单抗 （10 mg/kg） 静脉注射, 每 21天一次, 共 3 周期。对最初 16 例患者给予莫西沙星 （400 mg口服） 治疗 （该药与轻度 QT 间期延长有关） 作为阳性对照。在第 3 周期中的多个时间点对心电图连续进行三次检测以比较 QTcF 相对基线的延长恶化情况。
结果. 66 例患者接受了治疗, 其中 51 例患者完成了 ≥9 周治疗, 可进行完整的 QTcF 评价周期。每个时间点的 QTcF 相对基线变化的最小二乘均值的 90% 双侧置信区间上限均低于 10 毫秒。浓度-QTcF 分析显示雷莫芦单抗浓度与 QTcF 相对基线的变化值之间呈肉眼可见但无统计学意义的负相关性。
结论. 雷莫芦单抗10 mg/kg每21天给药一次、共3周期治疗, 不会对QTcF延长造成具有统计学或临床意义的影响。The Oncologist2016;21:402–403
Trial registration: ClinicalTrials.gov NCT01017731.
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