Authors' Affiliations: Phase I Clinical Trials Program, Department of Investigational Cancer Therapeutics; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Clinical Medicine, Hemocentro da Unicamp, University of Campinas, Sao Paulo, Brazil; Karmanos Cancer Institute/Wayne State University, Detroit, Michigan; and Department of Medicine, University of California, San Diego, La Jolla, California.
Clin Cancer Res. 2014 Jan 15;20(2):281-8. doi: 10.1158/1078-0432.CCR-13-2103. Epub 2013 Nov 4.
Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.
I 期临床试验使用少量患者来确定最大耐受剂量 (MTD) 和新药物的安全性。我们比较了 I 期和注册试验的数据，以确定早期试验是否能预测后期安全性和最终剂量。我们在美国食品和药物管理局 (FDA) 网站上搜索了非儿科癌症批准的药物（1990 年 1 月至 2012 年 10 月）。比较了 I 期推荐的 II 期剂量 (R2PD) 和毒性与后期试验的剂量和安全性。在 85 项匹配试验中的 62 项（73%）中，后期试验的剂量在 R2PD 的 20%以内。在多变量分析中，靶向药物的 I 期试验对最终批准剂量的预测性较低（OR，针对靶向药物和其他类别的 R2PD 采用±20%的目标，为 0.2；P=0.025）。在后期试验的 530 种临床相关毒性中，70%（n=374）在 I 期描述过。观察到 I 期患者数量增加（最多 60 例）与描述未来临床相关毒性的能力之间存在显著关系（P=0.0032）。在后期试验的 28505 例患者中，与药物相关的死亡率为 1.41%。结论：基于 I 期试验的剂量与后期试验中较低的毒性相关死亡率相关。预测相关毒性的能力与初始 I 期试验的患者数量相关。在评估的试验中，73%的试验最终批准剂量在 R2PD 的 20%以内。
