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.

Fig. 1.

Illustration of the PRT method for a hypothetical phase I trial. We assume that patients arrive in 6-day intervals. The horizontal axis represents the days since first patient enrolled into the trial. Each horizontal line is the time course of a patient. Numerical values preceding each time course represent the dose administered to that patient. Open circles indicate times at which patients were fully evaluated without toxicity and x's indicate toxicity times. Darker gray denotes periods when accrual was open. Lighter gray denotes periods when accrual was suspended.

Fig. 2.

Hazard functions and cumulative toxicity probabilities of the piecewise exponential distribution used in the simulations.

Fig. 3.

Comparison of toxicities observed using the PRT method and TITE-CRM under scenario 1 with varying accrual rates. Each toxicity percentage is labeled by the mean trial duration in years.