@article {Lemeche006136, author = {Charlotte Lemech and Keith Dredge and Darryn Bampton and Edward Hammond and Andrew Clouston and Nigel J Waterhouse and Amanda C Stanley and Lucie Leveque-El Mouttie and Grace M Chojnowski and Andrew Haydon and Nick Pavlakis and Matthew Burge and Michael P Brown and David Goldstein}, title = {Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors}, volume = {11}, number = {1}, elocation-id = {e006136}, year = {2023}, doi = {10.1136/jitc-2022-006136}, publisher = {BMJ Specialist Journals}, abstract = {Background Pixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers.Methods 3+3 dose escalation with microsatellite stable metastatic colorectal cancer (MSS mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC) expansion cohorts. Participants received pixatimod once weekly as a 1-hour intravenous infusion plus nivolumab every 2 weeks. Objectives included assessment of safety, antitumor activity, pharmacodynamics, and pharmacokinetic profile.Results Fifty-eight participants started treatment. The maximum tolerated dose of pixatimod was 25 mg in combination with 240 mg nivolumab, which was used in the expansion phases of the study. Twenty-one grade 3{\textendash}5 treatment-related adverse events were reported in 12 participants (21\%); one participant receiving 50 mg pixatimod/nivolumab had a treatment-related grade 5 AE. The grade 3/4 rate in the MSS mCRC cohort (n=33) was 12\%. There were no responders in the mPDAC cohort (n=18). In the MSS mCRC cohort, 25 participants were evaluable (initial postbaseline assessment scans \>6 weeks); of these, three participants had confirmed partial responses (PR) and eight had stable disease (SD) for at least 9 weeks. Clinical benefit (PR+SD) was associated with lower Pan-Immune-Inflammation Value and plasma IL-6 but increased IP-10 and IP-10/IL-8 ratio. In an MSS mCRC participant with PR as best response, increased infiltration of T cells, dendritic cells, and to a lesser extent NK cells, were evident 5 weeks post-treatment.Conclusions Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.Trial registration number NCT05061017.No data are available.}, URL = {https://jitc.bmj.com/content/11/1/e006136}, eprint = {https://jitc.bmj.com/content/11/1/e006136.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }