GSK-1795091

A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll‐like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti‐OX40 monoclonal antibody], GSK3359609 [anti‐ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty‐four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid‐study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose‐dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP‐10, IL10, IL1‐RA). Most patients (51/54; 94%) experienced ≥1 treatment‐emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti‐tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds.

Interest in Toll-like receptor (TLR) agonists for cancer treatment has been renewed after promising preliminary clinical data in combination with checkpoint inhibitors. This first-in-human study assessed the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenous GSK1795091, a synthetic TLR4 agonist, in healthy volunteers as a precursor to evaluation in patients with cancer.

Healthy participants were randomized (1:3; double-blinded manner) to receive placebo or a single intravenous injection of GSK1795091 at doses of 7-100 ng. The primary objective was to evaluate the safety and tolerability of GSK1795091; secondary and exploratory objectives were to characterize GSK1795091 PK and PD properties.

Forty participants received study treatment (10 received placebo and 30 received GSK1795091). Overall, 3 of the 10 participants (30%) who received placebo and 16 of the 30 (53%) who received GSK1795091 experienced ≥1 adverse event (AE). The most common AEs were influenza-like illness, headache, back pain, and increased body temperature. One participant experienced late-occurring AEs (alanine aminotransferase and aspartate aminotransferase increases), considered possibly related to GSK1795091. No serious AEs were reported. GSK1795091 PK properties were characterized by dose proportional increase in exposure. Transient and dose-dependent changes in induced cytokine and chemokine concentrations and immune cell counts were observed 1-4 h after GSK1795091 administration and returned to baseline within 24 h.

Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer. ClinicalTrials.gov identifier: NCT02798978.