Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE

Katrina Walker; Samantha Hinsley; Rachel Phillip; Jamie B. Oughton; Geraldine Murden; Anthony J. Chalmers; Corinne Faivre-Finn; Alastair Greystoke; Sarah R. Brown; M. Forster; K. Franks; A. Gilbert; G. G. Hanna; N. Hannaway; S. Harrow; T. Haswell; C. Hiley; M. Krebs; A. Salem; D. Sebag-Montefiore; P. Shaw; C. Twelves; G. Walls; R. Young; On behalf of the CONCORDE Investigators

doi:10.1200/PO.22.00133

Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE

Katrina Walker, Samantha Hinsley, Rachel Phillip, Jamie B. Oughton, Geraldine Murden, Anthony J. Chalmers, Corinne Faivre-Finn, Alastair Greystoke, Sarah R. Brown^*, M. Forster, K. Franks, A. Gilbert, G. G. Hanna, N. Hannaway, S. Harrow, T. Haswell, C. Hiley, M. Krebs, A. Salem, D. Sebag-MontefioreP. Shaw, C. Twelves, G. Walls, R. Young, On behalf of the CONCORDE Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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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.

Original language	English
Number of pages	12
Journal	JCO Precision Oncology
Volume	6
Early online date	29 Nov 2022
DOIs	https://doi.org/10.1200/PO.22.00133
Publication status	Published - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 by American Society of Clinical Oncology.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1200/PO.22.00133

Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 210 KBLicence: CC BY-NC-ND

Cite this

Walker, K., Hinsley, S., Phillip, R., Oughton, J. B., Murden, G., Chalmers, A. J., Faivre-Finn, C., Greystoke, A., Brown, S. R., Forster, M., Franks, K., Gilbert, A., Hanna, G. G., Hannaway, N., Harrow, S., Haswell, T., Hiley, C., Krebs, M., Salem, A., ... On behalf of the CONCORDE Investigators (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. https://doi.org/10.1200/PO.22.00133

@article{2b8281c1111d4af687f89b037e3ef978,

title = "Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE",

abstract = "PURPOSECONCORDE 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.",

author = "Katrina Walker and Samantha Hinsley and Rachel Phillip and Oughton, {Jamie B.} and Geraldine Murden and Chalmers, {Anthony J.} and Corinne Faivre-Finn and Alastair Greystoke and Brown, {Sarah R.} and M. Forster and K. Franks and A. Gilbert and Hanna, {G. G.} and N. Hannaway and S. Harrow and T. Haswell and C. Hiley and M. Krebs and A. Salem and D. Sebag-Montefiore and P. Shaw and C. Twelves and G. Walls and R. Young and {On behalf of the CONCORDE Investigators}",

note = "Publisher Copyright: {\textcopyright} 2022 by American Society of Clinical Oncology.",

year = "2022",

month = dec,

doi = "10.1200/PO.22.00133",

language = "English",

volume = "6",

journal = " JCO Precision Oncology",

issn = "2473-4284",

publisher = "American Society of Clinical Oncology",

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Walker, K, Hinsley, S, Phillip, R, Oughton, JB, Murden, G, Chalmers, AJ, Faivre-Finn, C, Greystoke, A, Brown, SR, Forster, M, Franks, K, Gilbert, A, Hanna, GG, Hannaway, N, Harrow, S, Haswell, T, Hiley, C, Krebs, M, Salem, A, Sebag-Montefiore, D, Shaw, P, Twelves, C, Walls, G, Young, R & On behalf of the CONCORDE Investigators 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, vol. 6. https://doi.org/10.1200/PO.22.00133

TY - JOUR

T1 - Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE

AU - Walker, Katrina

AU - Hinsley, Samantha

AU - Phillip, Rachel

AU - Oughton, Jamie B.

AU - Murden, Geraldine

AU - Chalmers, Anthony J.

AU - Faivre-Finn, Corinne

AU - Greystoke, Alastair

AU - Brown, Sarah R.

AU - Forster, M.

AU - Franks, K.

AU - Gilbert, A.

AU - Hanna, G. G.

AU - Hannaway, N.

AU - Harrow, S.

AU - Haswell, T.

AU - Hiley, C.

AU - Krebs, M.

AU - Salem, A.

AU - Sebag-Montefiore, D.

AU - Shaw, P.

AU - Twelves, C.

AU - Walls, G.

AU - Young, R.

AU - On behalf of the CONCORDE Investigators

PY - 2022/12

Y1 - 2022/12

N2 - PURPOSECONCORDE 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.

AB - PURPOSECONCORDE 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.

U2 - 10.1200/PO.22.00133

DO - 10.1200/PO.22.00133

M3 - Article

C2 - 36446040

AN - SCOPUS:85188319933

SN - 2473-4284

VL - 6

JO - JCO Precision Oncology

JF - JCO Precision Oncology

ER -

Implementation of the time-to-event continuous reassessment method design in a phase I platform trial testing novel radiotherapy-drug combinations-CONCORDE

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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