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.

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-alpha, 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/m(2); higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels > or =0.6 mg/m(2). 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/m(2) 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.

• Authors: Arkadiusz Z Dudek, Carla Yunis, Lester I Harrison, Sandeep Kumar, Ronald Hawkinson, Sarah Cooley, John P Vasilakos, Kevin S Gorski, Jeffrey S Miller
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 23 Pg. 7119-25 (Dec 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 18056192 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide
• Quinolines
• Sulfonamides
• TLR7 protein, human
• Toll-Like Receptor 7

Topics

• Adult
• Aged
• Aged, 80 and over
• Cell Line
• Cohort Studies
• Cytokines (immunology)
• Dendritic Cells (drug effects, immunology)
• Drug Administration Schedule
• Female
• Humans
• Immunity, Innate (drug effects)
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, immunology, metabolism)
• Quinolines (administration & dosage, adverse effects, pharmacokinetics)
• Sensitivity and Specificity
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)
• Toll-Like Receptor 7 (agonists)