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. Issue 1 (25th September 2018)

• Record Type: Journal Article
• Authors: Tran, Ben; Carvajal, Richard D.; Marabelle, Aurelien; Patel, Sandip Pravin; LoRusso, Patricia M.; Rasmussen, Erik; Juan, Gloria; Upreti, Vijay V.; Beers, Courtney; Ngarmchamnanrith, Gataree; Schöffski, Patrick
• Is Part Of: Journal for immunotherapy of cancer. Volume 6:Issue 1(2018)
• Publication Date: 2018-09-25
• Subjects: Glucocorticoid-induced TNFR-related protein -- Antibodies, monoclonal -- Clinical trial, phase 1 -- Dose, maximum tolerated -- Agonistic antibody; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-018-0407-x
• Languages: English
• ISSNs: 2051-1426

Abstract

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 .