Abstract 77P
Background
CONCORDE is a phase I platform study in NSC lung cancer testing different DNA damage response inhibitor (DDRi) RT combinations to identify the recommended phase II dose of DDRis. It is challenging to estimate toxicity rates and attribute toxicities to DDRi and/or RT, due to the lack of toxicity data on contemporary RT. We outline how we overcame the challenge of toxicity estimation and attribution.
Methods
A concurrent RT only calibration arm is included in CONCORDE. Once allocated to a study arm, patients are randomised between RT+/-DDRi (Table 77P). An allocation ratio of 1:1 was used initially. Dose limiting toxicities (DLT) and DLT rates presented for RT-only patients to the Safety Review Committee alongside those for RT+DDRi patients for comparison. Differences in DLT rates between original estimates and observed rates for RT only patients may indicate a need to adjust target DLT rates to inform dose escalation; differences between RT only rates and RT+DDRi rates may inform decisions around attribution. The addition of durvalumab in two arms will also inform the attribution of additional toxicity due to immunotherapy. Table: 77P
Treatment within each study arm
| Study arm | 6 week RT period | 1 year consolidation period |
| CONCORDE-A | Olaparib+RT | No treatment |
| RT only | ||
| CONCORDE-B | AZD1390+RT | |
| RT only | ||
| CONCORDE-C | Ceralasertib+RT | Cerelasertib + durvalumab |
| RT only | Durvalumab | |
| CONCORDE-E | AZD5305+RT | Durvalumab |
| RT only |
Results
CONCORDE opened to recruitment in April 2021. Recruitment was initially slow, resulting in limited data to inform dose escalation decisions. 10 patients were recruited to the RT only arm after 9 months across the arms, with a DLT rate of 10%. This was comparative to the expected DLT rate of 25% and randomisation allocation was changed to 3:1. As of 01/11/23 20 RT only patients have been treated, with a current DLT rate of 6% (95%CI: 0.1-27.3%), in line with prior expectations.
Conclusions
Pooling RT only patients across arms to estimate DLT rates presents a useful concurrent comparator to put the estimated DLT rate for informing dose escalation into context, and the rate in RT+DDRi patients to help attribute toxicity to the combination of DDRi and thoracic RT. The platform design necessitates fewer comparator patients, compared with multiple standalone comparison design trials.
Clinical trial identification
ISRCTN10142971, NCT04550104.
Editorial acknowledgement
Legal entity responsible for the study
University of Leeds.
Funding
Cancer Research UK and AstraZeneca.
Disclosure
O. Ojo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Invited Speaker: MSD, Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Personal, Advisory Role: National Institute for Health and Clinical Excellence; Non-Financial Interests, Personal, Leadership Role, Steering Committee member: British Thoracic Oncology Group; Other, Personal, Other, Clinical Lead for Cancer (paid position): North East England and Yorkshire Genomic Laboratory Hub. C. Faivre-Finn: Financial Interests, Institutional, Other, research-related advisory, Steering Committee, lectures: AstraZeneca; Financial Interests, Institutional, Other, research-related projects, advisory: Elekta; Financial Interests, Institutional, Other, Research-related Funding: MSD. P.H. Shaw: Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Advisory Role: BMS, Takeda; Financial Interests, Personal, Other, Travel, accommodation expenses: Takeda; Financial Interests, Personal, Royalties: Cellesce Ltd. K. Franks: Financial Interests, Personal, Full or part-time Employment: Genesis Care UK; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Research Grant: Yorkshire Cancer Research; Financial Interests, Institutional, Training: AstraZeneca, Boehringer Ingelheim, Elekta, Pierre Fabre, Novartis, Roche, Takeda; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Amgen, Boehringer Ingelheim, Bristol-Meyers-Squibb, Lilly, Roche, Takeda. C. Hiley: Financial Interests, Personal, Advisory Role: GenesisCare UK, AstraZeneca. A. Chalmers: Financial Interests, Institutional, Research Grant: Duke Street Bio, Exscientia, Benevolent AI; Financial Interests, Personal, Advisory Role: Duke Street Bio, Benevolent AI, Storm Therapeutics. All other authors have declared no conflicts of interest.