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

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 participate

All 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 publication

All patients provided written, informed consent.

Competing interests

BT 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.

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Figures

Fig. 1

Mean (± SD) pharmacokinetic profile of AMG 228 following intravenous administration of AMG 228 every 3 weeks. Blood samples were collected predose, at the end of infusion, and postdose over the 3-week dosing interval during treatment cycles

Fig. 2

Best change from baseline in the sum of longest diameters of target lesions. CRC, colorectal cancer; HirPD, immune-related progressive disease; irSD, immune-related stable disease. aPatient experienced clinical progression with new brain metastasis (off schedule scan) after the primary lesions showed decreases in size. bBecause patient’s only postbaseline scan was an abdominal CT. CRC, colorectal cancer; NSCLC, non–small-cell lung cancer; SCCHN, squamous cell carcinoma of the head and neck; TCC, transitional carcinoma of the bladder

Fig. 3

Pharmacodynamic assessment of target coverage and T cell activation. a flow cytometry analysis of GITR expression among peripheral blood Tregs pretreatment and posttreatment. b immunohistochemistry assessment of GITR expression and T cell activation in tumor biopsies pretreatment and posttreatment. c immunohistochemistry evidence of immune modulation following treatment (cycle 3, day 43) versus screening in a colorectal cancer biopsy. aLines not visible for 7 patients due to lack of GITR+ cells at pretreatment