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Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs

A partir de données portant sur les molécules ayant bénéficié d'une autorisation de mise sur le marché par l'autorité réglementaire américaine entre 1990 et 2012 pour le traitement de cancers non pédiatriques, cette étude compare les doses recommandées en conclusion des essais de phase I et les doses finalement autorisées

Phase I trials utilize 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 if early trials predicted later safety and final dose. We searched the US Food and Drug Administration (FDA) website for drugs approved in non-pediatric 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 (Odds Ratio [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 revelant 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.

Clinical Cancer Research , résumé, 2013

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