Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples

Abstract

Background: Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. Methods: The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant's dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies.

Adaptive Phase 1 Design in Radiation Therapy Trials

“…Despite these challenges, designing and executing early-phase trials using adaptive designs is achievable and effective. Design and implementation complexities have been mitigated in recent years thanks to guidance documents such as that of van Werkhoven et al 34 and available software such as https://sph.umich.edu/ccb/tite-resources. html.…”

Practical recommendations for implementing a Bayesian adaptive phase I design during a pandemic

“…There are an increasing number of resources (to which this work hopes to contribute) on how model-based dose-finding can be implemented [ 19 ]. While the first programming of such designs might be time-consuming for a statistician without prior experience in Bayesian methods, and, specifically, MCMC implementation, we note that it is becoming more common for authors to provide their code for the methods implementation, which may be used a good starting point.…”

“…However, the uptake of these new methods has been slow [ 11 ] and several obstacles to their use have been identified, including software, knowledge, and implementation [ 12 – 14 ]. To address some of these challenges, several software solutions have been described and made available [ 15 , 16 ] and publications describing these methods [ 17 ] or experiences using them [ 18 , 19 ] have been published in recent years.…”

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations—CONCORDE

“…A challenge of dose-finding trials of RT interventions is that commonly used designs 17 such as the 3 + 3 design and continual reassessment method (CRM) are not appropriate for this setting, 18 because of the need to evaluate late toxic effects of RT. An extension to the CRM, the time-to-event continual reassessment method (TiTE-CRM), allows continued recruitment while accruing follow-up for participants currently on trial.…”

“… 19 This time-to-event extension uses weights to represent partial follow-up of participants and allows for greater efficiency by allowing robust estimation of the recommended phase II dose (RP2D) when late-onset toxicities are present, thus lending itself to the RT setting. 10 , 18 Usage of TiTE-CRM methodology has become increasingly popular, with various trials having implemented the TiTE-CRM, in the RT combination setting 20 - 24 and more widely. 25 - 27 …”