A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monothera...

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Veröffentlicht in:British journal of cancer Jg. 118; H. 8; S. 1035 - 1041
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.04.2018
Schlagworte:
Cancer
Cell activation
Disease control
Immune response
Immunomodulation
Immunomodulators
Innate immunity
Intravenous administration
IP-10 protein
Monocyte chemoattractant protein 1
Pharmacodynamics
Pharmacokinetics
Solid tumors
T cell receptors
Tumor necrosis factor-α
Tumors
γ-Interferon
ISSN:0007-0920, 1532-1827, 1532-1827
Online-Zugang:Volltext
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Zusammenfassung:PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. 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. 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. 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-018-0006-0