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

PURPOSE: CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial.

METHODS

Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm.

RESULTS

The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology.

CONCLUSION

The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.