All the previously mentioned designs require that the toxicity outcome in each patient, or cohort of patients, be observed before more patients are entered. However, in certain situations such as radiotherapy or chemoprevention studies, interest may focus on late-onset toxicities as well as short-term effects, and the current designs would require an inordinate period of time to complete the study. Cheung and Chappell21 have therefore proposed an extension of the CRM that incorporates the time to toxicity in each patient, which they termed TITE-CRM. The main idea is as follows. Suppose toxic events occurring anywhere up to T time units from administration of therapy are of interest. Rather than waiting for each cohort of patients to be followed for this length of time (T = 6 months in their example), one could enter new patients at, say, half-month intervals. As in the CRM, the first patient is assigned to a dose level based on prior information or, as in the modified CRM, to the lowest candidate dose. The single-parameter logistic model or other suitable dose-response model is assumed, with p(x) corresponding to the probability that an individual receiving dose x will experience a DLT by time T. Then, if an individual has been followed for u less than T time units, the probability of a toxic event is simply taken to be g(x, u) = u/T • p(x) At the time the next patient(s) is (are) to be enrolled, the observed toxicities and follow-up times of patients already entered are used to form the posterior estimate of b, and the dose level for the next patient(s) is selected according to the usual CRM or modified CRM criteria. Simulation studies showed that TITECRM produced results comparable to its CRM counterpart, while significantly reducing the average trial duration.21 The only downside was that TITE-CRM tended to generate slightly more AEs. As might be expected, differences were greatest for situations in which AEs tend to occur near the end of the observation period, because escalation may occur before any such events are observed.

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