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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours
BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary effica...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931096/ https://www.ncbi.nlm.nih.gov/pubmed/29531325 http://dx.doi.org/10.1038/s41416-018-0006-0 |
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author | Dredge, Keith Brennan, Todd V. Hammond, Edward Lickliter, Jason D. Lin, Liwen Bampton, Darryn Handley, Paul Lankesheer, Fleur Morrish, Glynn Yang, Yiping Brown, Michael P. Millward, Michael |
author_facet | Dredge, Keith Brennan, Todd V. Hammond, Edward Lickliter, Jason D. Lin, Liwen Bampton, Darryn Handley, Paul Lankesheer, Fleur Morrish, Glynn Yang, Yiping Brown, Michael P. Millward, Michael |
author_sort | Dredge, Keith |
collection | PubMed |
description | BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion. RESULTS: Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)—hypertension (2), epistaxis (1)—occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1. CONCLUSION: PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies. |
format | Online Article Text |
id | pubmed-5931096 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59310962019-04-15 A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours Dredge, Keith Brennan, Todd V. Hammond, Edward Lickliter, Jason D. Lin, Liwen Bampton, Darryn Handley, Paul Lankesheer, Fleur Morrish, Glynn Yang, Yiping Brown, Michael P. Millward, Michael Br J Cancer Article BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion. RESULTS: Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)—hypertension (2), epistaxis (1)—occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1. CONCLUSION: PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies. Nature Publishing Group UK 2018-03-13 2018-04-17 /pmc/articles/PMC5931096/ /pubmed/29531325 http://dx.doi.org/10.1038/s41416-018-0006-0 Text en © Cancer Research UK 2018 https://creativecommons.org/licenses/by/4.0/Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0). |
spellingShingle | Article Dredge, Keith Brennan, Todd V. Hammond, Edward Lickliter, Jason D. Lin, Liwen Bampton, Darryn Handley, Paul Lankesheer, Fleur Morrish, Glynn Yang, Yiping Brown, Michael P. Millward, Michael A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title | A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title_full | A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title_fullStr | A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title_full_unstemmed | A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title_short | A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours |
title_sort | phase i study of the novel immunomodulatory agent pg545 (pixatimod) in subjects with advanced solid tumours |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931096/ https://www.ncbi.nlm.nih.gov/pubmed/29531325 http://dx.doi.org/10.1038/s41416-018-0006-0 |
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