CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

Abstract

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

A scoping review of small animal image-guided radiotherapy research: Advances, impact and future opportunities in translational radiobiology

“…For example, a study from the group at Queen’s University Belfast assessed the impact of AZD6738, an inhibitor of the ataxia telangiectasia related-3(ATRP) kinase in the DNA damage response, on tumor efficacy and late toxicity in the lung [30] . This study directly supported the translation of this approach to evaluate the safety of inhibitors of the DNA damage response in patients with non-small cell lung cancer through the CONDORDE trial (NCT04550104) [31] , [32] , [33] . Similarly, a study from Maastricht University demonstrated the efficacy of nintedanib in reducing radiation-induced lung fibrosis that subsequently led to multiple clinical trials (NCT02452463; NCT02496585) [34] , [35] .…”

Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer

“…However, platform or umbrella trials provide an opportunity to study multiple targeted therapies in the same disease area in a more efficient and scientifically rich manner [16] . A multi-arm phase IB platform study to determine the recommended phase II doses and safety profiles of up to five DNA damage response inhibitors given in combination with fixed dose curative-intent RT in patients with stage IIB/III NSCLC was recently funded by Cancer Research UK [35] . This platform will allow the study of multiple drugs in combination with RT in an efficient and scientifically rich manner with a planned associated translational research programme.…”

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

“…CONCORDE is designed using a Bayesian adaptive modelbased approach to dose escalation, with separate TiTE-CRM models for each experimental arm. 29 The primary objective is to determine the RP2D for each DDRi in combination with radical thoracic RT of 60 Gy in 30 fractions, on the basis of observed DLTs, defined in the Data Supplement. The DLT monitoring period is 13.5 months from the start of RT, divided into two periods: acute (up to 4.5 months post-RT start) and long (4.5 months to 13.5 months post-RT start).…”

“…The protocol is described in elsewhere. 29 Here, we report in detail the statistical design and implementation of the TiTE-CRM (ISRCTN10142971).…”