title: Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs.
abstract: Purpose:Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design:We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results:We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1-4.0;P= 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0-2.9;P= 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5-5.7;P= 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6-5.2;P= 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2-8.8;P< 0.001).Conclusions:The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association.Clin Cancer Res; 23(15); 4020-6. ©2017 AACR.
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Diogo D G
authors.initials: DDG
authors.lastname: Bugano
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.affiliation: Centro de Oncologia do Paraná, Curitiba, Brazil.
authors.forename: Denis L F
authors.initials: DLF
authors.lastname: Jardim
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Alona
authors.initials: A
authors.lastname: Zer
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Albiruni R A
authors.initials: ARA
authors.lastname: Razak
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. dshong@mdanderson.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic / Q000592:standards; D017322:Clinical Trials, Phase II as Topic / Q000592:standards; D015331:Cohort Studies; D006801:Humans; D016015:Logistic Models; D008495:Medical Oncology / Q000592:standards; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology; D011336:Probability; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents