title: Monitoring late-onset toxicities in phase I trials using predicted risks.
abstract: Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average.
authors: Department of Biostatistics, MD Anderson Cancer Center, Houston, TX 77030, USA. bbekele@mdanderson.org
authors: B Nebiyou
authors: BN
authors: Bekele
authors: Yuan
authors: Y
authors: Ji
authors: Yu
authors: Y
authors: Shen
authors: Peter F
authors: PF
authors: Thall
mesh_terms: D001499:Bayes Theorem; D001932:Brain Neoplasms / Q000503:physiopathology / Q000532:radiotherapy; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004341:Drug Evaluation / Q000379:methods; D016903:Drug Monitoring / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis*; D006801:Humans; D008390:Markov Chains; D020714:Maximum Tolerated Dose; D009010:Monte Carlo Method; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects; D012107:Research Design; D012306:Risk; D013995:Time; D016896:Treatment Outcome
chemical_list: D011838:Radiation-Sensitizing Agents