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

作者：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

来源：British Journal of Cancer, 2018, 118(8): 1035-1041.

DOI：10.1038/s41416-018-0006-0

• SPONTANEOUSLY HYPERTENSIVE-RATS
• INFILTRATING MACROPHAGES
• HEPARANASE INHIBITOR
• PANCREATIC-CANCER
• RECEPTOR 9
• CELLS
• ANGIOGENESIS
• IMMUNITY
• MODELS
• GROWTH

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 IFN gamma, TNF alpha, 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.

• 出版日期2018-4