Monitoring Late Onset Toxicities in Phase I Trials Using Predicted Risks
by
B. Nebiyou Bekele
University of Texas M. D. Anderson Cancer Center
Coauthors: Yuan Ji, Yu Shen, and Peter F Thall

Late onset toxicities are a serious concern in many phase I oncology 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 late onset 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). We propose a Bayesian dose-finding method similar to the TITE-CRM in that 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 re-started, 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.

Date received: April 3, 2007