Jordan Emma J, Spicer James, Sarker Debashis
School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
Oncotarget. 2018 Sep 21;9(74):33961-33971. doi: 10.18632/oncotarget.26104.
Grade 3 and 4 adverse events (AEs) during cycle 1 are traditionally used for dose escalation decisions in Phase I oncology trials. With molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered increasingly relevant.
We conducted a retrospective analysis of AEs in patients enrolled onto relevant phase I trials of MTAs and cytotoxic combinations (CCs) at our UK centre between 2006 and 2016. All AEs in the first six cycles deemed at least 'possibly related' were recorded.
A total of 912 AEs were identified in 127 patients across 15 trials. Mean AE totals for CCs or MTAs respectively was 4.7 versus 3.0 in cycle 1, 3.8 versus 2.8 in cycles 2-6. Patients on CCs had higher mean AEs in six cycles compared to those on MTAs (8.5 vs. 5.7, p = 0.0005). For patients experiencing grade 3 AEs, 58% (CCs) and 60% (MTAs) occurred for the first time after cycle 1.
Overall AE incidence was lower in MTAs than CCs across six cycles. For MTAs, more frequent incidence of first grade 3/4 AEs after cycle 1 supports incorporation of delayed AEs into recommendations for Phase 2 dosing.
在肿瘤学I期试验中，传统上使用第1周期的3级和4级不良事件（AE）来做出剂量递增决策。对于分子靶向药物（MTA），对较低级别的AE以及后续周期的AE进行评估越来越受到重视。
我们对2006年至2016年期间在英国中心参加MTA和细胞毒性联合用药（CC）相关I期试验的患者的AE进行了回顾性分析。记录了前六个周期中所有被认为至少“可能相关”的AE。
在15项试验的127名患者中总共识别出912例AE。CC组和MTA组在第1周期的平均AE总数分别为4.7和3.0，在第2 - 6周期分别为3.8和2.8。与接受MTA治疗的患者相比，接受CC治疗的患者在六个周期中的平均AE更高（8.5对5.7，p = 0.0005）。对于发生3级AE的患者，58%（CC组）和60%（MTA组）在第1周期后首次出现。
在六个周期中，MTA的总体AE发生率低于CC。对于MTA，第1周期后首次出现3/4级AE的频率更高，这支持将延迟出现的AE纳入2期给药建议中。
