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
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 ca...
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| Format: | Article |
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e006136.full |
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| _version_ | 1832582762150756352 |
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| author | Matthew Burge David Goldstein Andrew Haydon Nick Pavlakis Charlotte Lemech Edward Hammond Darryn Bampton Keith Dredge Michael P Brown Andrew Clouston Nigel J Waterhouse Amanda C Stanley Lucie Leveque-El Mouttie Grace M Chojnowski |
| author_facet | Matthew Burge David Goldstein Andrew Haydon Nick Pavlakis Charlotte Lemech Edward Hammond Darryn Bampton Keith Dredge Michael P Brown Andrew Clouston Nigel J Waterhouse Amanda C Stanley Lucie Leveque-El Mouttie Grace M Chojnowski |
| author_sort | Matthew Burge |
| collection | DOAJ |
| description | 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 3–5 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. |
| format | Article |
| id | doaj-art-9084358ebd5841eb853afac834f15155 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9084358ebd5841eb853afac834f151552025-01-29T10:00:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-006136Phase 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 tumorsMatthew Burge0David Goldstein1Andrew Haydon2Nick Pavlakis3Charlotte Lemech4Edward Hammond5Darryn Bampton6Keith Dredge7Michael P Brown8Andrew Clouston9Nigel J Waterhouse10Amanda C Stanley11Lucie Leveque-El Mouttie12Grace M Chojnowski13Medical Oncology, The Royal Brisbane and Women’s Hospital, Brisbane, Queensland, AustraliaDepartment of Otolaryngology and Head and Neck Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada3Alfred Hospital, Melbourne, VIC, AustraliaMedical Oncology, Genesis Care, North Shore Health Hub, St Leonards, New South Wales, AustraliaScientia Clinical Research Ltd, Sydney, New South Wales, AustraliaBioPharmaceuticals Medical, AstraZeneca, Gaithersburg, Maryland, USAZucero Therapeutics Ltd, Brisbane, Queensland, AustraliaZucero Therapeutics Ltd, Brisbane, Queensland, AustraliaDepartment of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaDepartment of Pathology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, AustraliaQIMR Berghofer Medical Research Institute, Herston, Queensland, AustraliaQIMR Berghofer Medical Research Institute, Herston, Queensland, AustraliaQIMR Berghofer Medical Research Institute, Herston, Queensland, AustraliaQIMR Berghofer Medical Research Institute, Herston, Queensland, AustraliaBackground 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 3–5 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.https://jitc.bmj.com/content/11/1/e006136.full |
| spellingShingle | Matthew Burge David Goldstein Andrew Haydon Nick Pavlakis Charlotte Lemech Edward Hammond Darryn Bampton Keith Dredge Michael P Brown Andrew Clouston Nigel J Waterhouse Amanda C Stanley Lucie Leveque-El Mouttie Grace M Chojnowski 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 Journal for ImmunoTherapy of Cancer |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/11/1/e006136.full |
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