First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer

Arkadiusz Z Dudek, Carla Yunis, Lester I. Harrison, Sandeep Kumar, Ronald Hawkinson, Sarah A Cooley, John P. Vasilakos, Kevin S. Gorski, Jeffrey S Miller

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Purpose: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans. Experimental Design: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles. Results: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m 2. Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m2; higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-α, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels ≥0.6 mg/m2. Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen. Conclusions: 852A was safely administered i.v. at doses up to 1.2 mg/m2 thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.

Original languageEnglish (US)
Pages (from-to)7119-7125
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number23
DOIs
StatePublished - Dec 1 2007

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