First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors.

Background: Inducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation by T-cell receptors. ICOS stimulation downstream effects include activation of conventional CD4+cells and cytotoxic CD8+cells, resulting in a durable antitumor response in preclinical models.

Methods: As part of a larger first-in-human study (GSK Study 204691), this study focused on 2 cohorts of 25 and 67 participants enrolled in a dose escalation and pharmacokinetic/pharmacodynamic (PK/PD) analysis of the ICOS agonist feladilimab (GSK3359609) as monotherapy. For these cohorts, the objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) or maximum administered dose of feladilimab. Additional objectives included determining the recommended dose of feladilimab for further exploration, characterizing the PK properties, and immunogenicity.

Results: Feladilimab was examined over a range of 4 logs from 0.001 mg/kg to 10 mg/kg, and no MTD was established. Adverse events were manageable and consistent with those observed with other immunomodulatory treatments; fatigue, fever, and anemia were the most common events. PK showed a peak value 1 hour following infusion. Accumulation ratio ranged from 1.4 to 2.5 and was generally consistent with expected patterns of accumulation for a monoclonal antibody, and the drug showed linear dose proportionality. ICOS receptor occupancy was maximal at doses>0.1 mg/kg. Based on the collected data, doses of 0.3 and 1.0 mg/kg were selected for further exploration.

Conclusions: This study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile.