title: Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs.
abstract: 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.
authors.affiliation: 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.
authors.forename: Denis L
authors.initials: DL
authors.lastname: Jardim
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorusso
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D017277:Drug Approval; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents