Implementation of the time-to-event continuous reassessment method design in a phase i platform trial testing novel radiotherapy-drug combinations
Oughton, J. B.
Chalmers, A. J.
Brown, S. R.
AffiliationClinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, England
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AbstractPurpose: 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.
CitationWalker K, Hinsley S, Phillip R, Oughton JB, Murden G, Chalmers AJ, et al. Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE. JCO Precis Oncol. 2022 Nov;6:e2200133. PubMed PMID: 36446040. Epub 2022/11/30. eng.
JournalJCO Precision Oncology
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