Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors
Ben Tran, Richard D Carvajal, Aurelien Marabelle, Sandip Pravin Patel, Patricia M LoRusso, Erik Rasmussen, Gloria Juan, Vijay V Upreti, Courtney Beers, Gataree Ngarmchamnanrith, Patrick Schöffski, Ben Tran, Richard D Carvajal, Aurelien Marabelle, Sandip Pravin Patel, Patricia M LoRusso, Erik Rasmussen, Gloria Juan, Vijay V Upreti, Courtney Beers, Gataree Ngarmchamnanrith, Patrick Schöffski
Abstract
Background: 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.
Methods: AMG 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.
Results: Thirty 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.
Conclusions: In 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 registration: ClinicalTrials.gov, NCT02437916 .
Keywords: Agonistic antibody; Antibodies, monoclonal; Clinical trial, phase 1; Dose, maximum tolerated; Glucocorticoid-induced TNFR-related protein.
Conflict of interest statement
Ethics approval and consent to participateAll procedures were approved by the following institutional review boards or ethics committees: Commissie Medische Ethiek van de Universitaire Ziekenhuizen KU Leuven; Ethikkommision; Comité de Protection des Personnes Ile de France; Columbia University IRB; UCSD Human Research Protections Program; WIRB; and Melbourne Health Human Research Ethics Committee.
Consent for publicationAll patients provided written, informed consent.
Competing interestsBT has received a grant, consulting fees, and honoraria from Amgen Inc. RDC is a consultant for AstraZeneca, Bristol-Myers Squibb, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Novartis, and Roche/Genentech, has served on clinical advisory boards for Aura Biosciences and Rgenix, and has served on a scientific advisory board for Chimeron. SPP has received research support from Amgen Inc. ER, GJ, VVU, and GN are employees of and own stock in Amgen Inc. At the time of this study, CB was an employee of Amgen Inc. AM, PML, and PS have no conflicts to disclose.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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