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

BackgroundPixatimod 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.Methods3+3 dose escalation with microsatellite stable metastatic colorectal canc...

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Published inJournal for immunotherapy of cancer Vol. 11; no. 1; p. e006136
Main Authors Lemech, Charlotte, Dredge, Keith, Bampton, Darryn, Hammond, Edward, Clouston, Andrew, Waterhouse, Nigel J, Stanley, Amanda C, Leveque-El Mouttie, Lucie, Chojnowski, Grace M, Haydon, Andrew, Pavlakis, Nick, Burge, Matthew, Brown, Michael P, Goldstein, David
Format Journal Article
LanguageEnglish
Published England BMJ Publishing Group Ltd 01.01.2023
BMJ Publishing Group LTD
BMJ Publishing Group
SeriesOriginal research
Subjects
Adenocarcinoma - pathology
Angiogenesis Inhibitors - therapeutic use
Antibodies
Anticoagulants
Biomarkers
Cancer
Cancer therapies
Chemokine CXCL10
Clinical/Translational Cancer Immunotherapy
Colorectal cancer
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Drug dosages
Drug Therapy, Combination
FDA approval
Humans
Immunomodulation
Immunotherapy
Ligands
Lymphocyte Activation
Metastasis
Microsatellite Repeats
Monoclonal antibodies
Nivolumab - pharmacology
Nivolumab - therapeutic use
Pancreatic cancer
Pancreatic Neoplasms
Radiation
Targeted cancer therapy
Toll-Like Receptor 9
Tumors
Australia
New South Wales Australia
Drug Therapy, Combination
Immunomodulation
Lymphocyte Activation
Immunotherapy
Online AccessGet full text

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Abstract BackgroundPixatimod 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.Methods3+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.ResultsFifty-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.ConclusionsPixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.Trial registration numberNCT05061017.
AbstractList BackgroundPixatimod 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.Methods3+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.ResultsFifty-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.ConclusionsPixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.Trial registration numberNCT05061017.
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.BACKGROUNDPixatimod 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.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.METHODS3+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.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.RESULTSFifty-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.Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.CONCLUSIONSPixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation.NCT05061017.TRIAL REGISTRATION NUMBERNCT05061017.
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.
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. 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. 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. Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation. NCT05061017.
Author Brown, Michael P
Chojnowski, Grace M
Burge, Matthew
Hammond, Edward
Lemech, Charlotte
Clouston, Andrew
Stanley, Amanda C
Waterhouse, Nigel J
Haydon, Andrew
Dredge, Keith
Pavlakis, Nick
Bampton, Darryn
Goldstein, David
Leveque-El Mouttie, Lucie
AuthorAffiliation 11 Medical Oncology , Prince of Wales Hospital , Sydney , New South Wales , Australia
7 Faculty of Medicine , University of Sydney , Sydney , New South Wales , Australia
6 Medical Oncology, Genesis Care , North Shore Health Hub , St Leonards , New South Wales , Australia
10 Centre for Cancer Biology , University of South Australia and SA Pathology , Adelaide , South Australia , Australia
8 Medical Oncology , The Royal Brisbane and Women’s Hospital , Brisbane , Queensland , Australia
2 Zucero Therapeutics Ltd , Brisbane , Queensland , Australia
3 Department of Pathology , Royal Brisbane and Women’s Hospital , Brisbane , Queensland , Australia
5 Medical Oncology , The Alfred Hospital , Melbourne , Victoria , Australia
1 Scientia Clinical Research Ltd , Sydney , New South Wales , Australia
4 QIMR Berghofer Medical Research Institute , Herston , Queensland , Australia
9 Cancer Clinical Trials Unit , Royal Adelaide Hospital , Adelaide , South Australia , Australia
AuthorAffiliation_xml – name: 2 Zucero Therapeutics Ltd , Brisbane , Queensland , Australia
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– name: 3 Department of Pathology , Royal Brisbane and Women’s Hospital , Brisbane , Queensland , Australia
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36634920$$D View this record in MEDLINE/PubMed
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Copyright Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Issue 1
Keywords Drug Therapy, Combination
Immunomodulation
Lymphocyte Activation
Immunotherapy
Language English
License This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Notes Original research
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content type line 23
ORCID 0000-0002-5796-1932
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PublicationSeriesTitle Original research
PublicationTitle Journal for immunotherapy of cancer
PublicationTitleAbbrev J Immunother Cancer
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  year: 2018
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  article-title: A phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours
  publication-title: Br J Cancer
  doi: 10.1038/s41416-018-0006-0
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  year: 2017
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  article-title: The heparanase inhibitor PG545 attenuates colon cancer initiation and growth, associating with increased p21 expression
  publication-title: Neoplasia
  doi: 10.1016/j.neo.2016.12.001
– volume: 18
  start-page: 3033
  year: 2022
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  article-title: Mitophagy: a new actor in the efficacy of chemo-immunotherapy
  publication-title: Autophagy
  doi: 10.1080/15548627.2022.2069439
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  doi: 10.1007/s10637-009-9245-5
– volume: 13
  year: 2021
  ident: 2024053113363480000_11.1.e006136.32
  article-title: Combination immunotherapies to overcome intrinsic resistance to checkpoint blockade in microsatellite stable colorectal cancer
  publication-title: Cancers
  doi: 10.3390/cancers13194906
– ident: 2024053113363480000_11.1.e006136.21
  doi: 10.1371/journal.pone.0052175
– ident: 2024053113363480000_11.1.e006136.29
  doi: 10.1038/sj.onc.1210911
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Snippet BackgroundPixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod...
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...
Background Pixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod...
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SubjectTerms Adenocarcinoma - pathology
Angiogenesis Inhibitors - therapeutic use
Antibodies
Anticoagulants
Biomarkers
Cancer
Cancer therapies
Chemokine CXCL10
Clinical/Translational Cancer Immunotherapy
Colorectal cancer
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Drug dosages
Drug Therapy, Combination
FDA approval
Humans
Immunomodulation
Immunotherapy
Ligands
Lymphocyte Activation
Metastasis
Microsatellite Repeats
Monoclonal antibodies
Nivolumab - pharmacology
Nivolumab - therapeutic use
Pancreatic cancer
Pancreatic Neoplasms
Radiation
Targeted cancer therapy
Toll-Like Receptor 9
Tumors
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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
URI https://jitc.bmj.com/content/11/1/e006136.full
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Volume 11
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