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

Walker, K; Hinsley, S; Phillip, R; Oughton, JB; Murden, G; Chalmers, AJ; Faivre-Finn, C; ... Young, R; + view all (2022) Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE. JCO Precision Oncology , 6 (6) , Article e2200133. 10.1200/PO.22.00133. Green open access

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Abstract

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.

Type: Article
Title: Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1200/PO.22.00133
Publisher version: http://dx.doi.org/10.1200/po.22.00133
Language: English
Additional information: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Humans, Carcinoma, Non-Small-Cell Lung, Clinical Trials, Phase I as Topic, Drug Combinations, Lung Neoplasms, Radiation Oncology, Randomized Controlled Trials as Topic, Research Design
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10190230
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