Title: CRUK/19/006 - CONCORDE: A Platform study of DNA Damage Response Inhibitors in COmbinatioN with COnventional RaDiothErapy in Non Small Cell Lung Cancer
Funder: Cancer Research UK

Abstract: Background: Lung cancer is the leading cause of cancer mortality with ~46,000 new cases diagnosed annually in the UK, of which ~85% are non-small cell lung cancer (NSCLC). In patients with locally advanced NSCLC (Stage IIB/III), radiotherapy can be used with curative intent. However, outcomes remain poor with ~15% 5-year survival following concurrent chemoradiotherapy (standard of care), dropping to 10% in patients receiving sequential chemoradiotherapy (received by 64% owing to tumour factors and/or comorbidities). A promising strategy based on the mechanism of radiotherapy (RT) cytotoxicity is combining DNA damage response inhibitors (DDRi) that act synergistically in pre-clinical models to enhance tumour cell killing. There is a paucity of novel drug–RT combination trials (only 6% of Phase I studies in NSCLC). There is an urgent need for innovative approaches to evaluate whether DDRi-RT combinations can improve outcomes in this potentially curative setting. Aims: CONCORDE is a first of its kind multi-arm Phase IB platform study to determine the recommended Phase II doses (RP2Ds) and safety profiles of up to five DDRi given in combination with fixed dose curative intent radiotherapy in participants with stage IIB/III NSCLC. This platform allows us to study multiple targeted therapies in an efficient and scientifically rich manner with a planned associated translational research programme. Methods: The CONCORDE study will enrol participants with stage IIB/III NSCLC and performance status (PS) 0-1 who are not suitable for surgery or concurrent chemoradiotherapy due to disease bulk, location or co-morbidities. Participants will be assigned to an individual DDRi arm based on predefined prioritisation schedules. Participants will then be randomised between DDRi-RT (n=30) versus RT only (n=10) per arm. The 50 RT alone patients will be pooled across the platform to provide robust contemporary toxicity data with modern treatment techniques. An adaptive model-based approach to dose escalation will be used for each DDRi independently (Time-To-Event Continual Reassessment Method), with decisions driven by occurrence of dose limiting toxicities up to 12 months. Archival tumour will be collected and serial blood samples taken to allow the planned translational research. How the results of this research will be used: RP2Ds of each agent with radiotherapy will be taken forward into later stage studies to formally evaluate efficacy. In order to maximise scientific outputs we have established a team of clinicians and translational scientists evaluating future patient selection for treatment and identifying novel measures of tumour response and normal tissue toxicity with DDRi-RT combinations.

Lay abstract: Background: Lung cancer is the leading cause of cancer mortality with ~46,000 new cases diagnosed annually in the UK, of which ~85% are non-small cell lung cancer (NSCLC). In patients with locally advanced NSCLC (Stage IIB/III), radiotherapy can be used with curative intent. However, outcomes remain poor with ~15% 5-year survival following concurrent chemoradiotherapy (standard of care), dropping to 10% in patients receiving sequential chemoradiotherapy (received by 64% owing to tumour factors and/or comorbidities). A promising strategy based on the mechanism of radiotherapy (RT) cytotoxicity is combining DNA damage response inhibitors (DDRi) that act synergistically in pre-clinical models to enhance tumour cell killing. There is a paucity of novel drug–RT combination trials (only 6% of Phase I studies in NSCLC). There is an urgent need for innovative approaches to evaluate whether DDRi-RT combinations can improve outcomes in this potentially curative setting. Aims: CONCORDE is a first of its kind multi-arm Phase IB platform study to determine the recommended Phase II doses (RP2Ds) and safety profiles of up to five DDRi given in combination with fixed dose curative intent radiotherapy in participants with stage IIB/III NSCLC. This platform allows us to study multiple targeted therapies in an efficient and scientifically rich manner with a planned associated translational research programme. Methods: The CONCORDE study will enrol participants with stage IIB/III NSCLC and performance status (PS) 0-1 who are not suitable for surgery or concurrent chemoradiotherapy due to disease bulk, location or co-morbidities. Participants will be assigned to an individual DDRi arm based on predefined prioritisation schedules. Participants will then be randomised between DDRi-RT (n=30) versus RT only (n=10) per arm. The 50 RT alone patients will be pooled across the platform to provide robust contemporary toxicity data with modern treatment techniques. An adaptive model-based approach to dose escalation will be used for each DDRi independently (Time-To-Event Continual Reassessment Method), with decisions driven by occurrence of dose limiting toxicities up to 12 months. Archival tumour will be collected and serial blood samples taken to allow the planned translational research. How the results of this research will be used: RP2Ds of each agent with radiotherapy will be taken forward into later stage studies to formally evaluate efficacy. In order to maximise scientific outputs we have established a team of clinicians and translational scientists evaluating future patient selection for treatment and identifying novel measures of tumour response and normal tissue toxicity with DDRi-RT combinations.

Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS