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Background: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC., Patients and Methods: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively., Results: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D., Conclusions: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2., Trial Registration: NCT03812796 (registered 23 rd January 2019)., Competing Interests: Disclosure DC received research funding from Clovis, Eli-Lilly, 4SC, Bayer, Celgene, Leap and Roche and sits on the scientific advisory board for OVIBIO. IC is on the advisory board of Eli-Lilly, Bristol Myers Squibb (BMS), MSD, Roche, Merck, AstraZeneca, OncXerna, Boehringer Ingelheim, Incyte, Astella, GSK, SOTIO, Eisai, Daiichi-Sankyo, Taiho, Servier, Seagen, Turning Point Therapeutics, Novartis, BioNTech, Takeda and Elevation Oncology; received research funding from Eli-Lilly and Janssen-Cilag; and honoraria from Eli-Lilly, Eisai, Servier and Roche. NS has served on advisory boards for Pfizer, Servier, AstraZeneca, MSD Oncology, Novartis, Guardant, GSK, Gilead, Seagen and Janssen; received research funding from Merck, AstraZeneca, BMS, Pfizer and Guardant Health; and honoraria from Merck, Novartis, MSD Oncology, Eli-Lilly, Pierre Fabre, Amgen, Eli-Lilly Bangladesh, GSK, Seagen, BMS, AstraZeneca and Servier. SR receives financial support from Boehringer, Merck, Servier and Bayer; has served on advisory boards for HOOKIPA, Bayer, BeiGene, AstraZeneca, Merck, Seagen and Servier. CF has received financial support from AAA and Servier. ES receives financial support from the NIHR Biomedical Research Centre in Oxford; receives grants and personal fees from Bristol Myers Squibb and AstraZeneca; receives personal fees from Amgen, Daiichi Sankyo, Mirati, Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks and BeiGene, outside the submitted work; receives nonfinancial support from Mirati; and is the European Organisation for Research and Treatment of Cancer Gastric Cancer Taskforce Chair and an Ireland Oesophagogastric Cancer Group Trustee. WM has consulting and advisory roles with Ipsen, Novartis, Pfizer, MSD, BMS and Servier; has been involved in the speakers’ bureau with Ipsen, Novartis, MSD and Servier; has travel grants from MSD, Ipsen, BMS and Servier; and institutional grants from Nordic and MSD. The other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK's first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS)., Methods: We are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022., Discussion: The trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it., Trial Registration: NCT04050345., (© 2023. The Author(s).)