Abstract
BackgroundThis open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor−related protein (GITR), in patients with refractory advanced solid tumors.MethodsAMG 228 was administered intravenously every 3 weeks (Q3W). Dose escalation was in two stages: single-patient cohorts (3, 9, 30, and 90 mg), followed by “rolling six” design (n = 2–6; 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs), AEs, and pharmacokinetics. Additional endpoints were objective response and pharmacodynamic response.ResultsThirty patients received AMG 228, which was well tolerated up to the maximum planned dose (1200 mg). No DLTs occurred; the MTD was not reached. The most common treatment-related AEs were fatigue (13%), infusion-related reaction (7%), pyrexia (7%), decreased appetite (7%), and hypophosphatemia (7%). Two patients had binding anti−AMG 228 antibodies (one at baseline); no neutralizing antibodies were detected. AMG 228 exhibited target-mediated drug disposition, and serum exposure was approximately dose proportional at 180–1200 mg and greater than dose proportional at 3–1200 mg. Doses > 360 mg Q3W achieved serum trough coverage for 95% in vitro GITR occupancy. Despite GITR coverage in peripheral blood and tumor biopsies, there was no evidence of T-cell activation or anti-tumor activity.ConclusionsIn patients with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), exhibited favorable pharmacokinetics, and provided target coverage indicating a pharmacokinetic profile appropriate for longer intervals. However, there was no evidence of T-cell activation or anti-tumor activity with AMG 228 monotherapy.Trial registrationClinicalTrials.gov, NCT02437916.
Highlights
This open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor−related protein (GITR), in patients with refractory advanced solid tumors
Agonistic antibodies or GITR ligand binding to GITR in concert with T cell receptor (TCR) stimulation causes activation of the MAPK/ERK pathway and NFkB, resulting in augmentation of T cell proliferation and proinflammatory cytokine production and enhanced anti-tumor effector function [5, 6], as well as resistance of CD4+ and CD8+ T cells to Regulatory T cell (Treg) suppression [4]
In conclusion, AMG 228 showed acceptable safety and favorable pharmacokinetics and serum target coverage as a monotherapy administered at intravenous doses up to 1200 mg Every 3 weeks (Q3W) in patients with advanced solid tumors
Summary
This open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor−related protein (GITR), in patients with refractory advanced solid tumors. Glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) is a TNF receptor superfamily costimulatory molecule expressed primarily by regulatory T cells (Treg), effector T cells, and natural killer cells that inhibits the suppressive activity of Tregs [1,2,3,4]. The objectives of the dose escalation of this open-label, first-in-human, phase 1 study were to evaluate the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228 in patients with advanced solid tumors
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