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J Immunother Cancer. 2018 Sep 25;6(1):93. doi: 10.1186/s40425-018-0407-x.

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.

Author information

1
Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia. Ben.Tran@petermac.org.
2
Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, New York, USA.
3
Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
4
INSERM U1015, Gustave Roussy, Villejuif, France.
5
Division of Hematology and Medical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
6
Department of Medical Oncology, Yale Cancer Center, New Haven, CT, USA.
7
Amgen Inc, Thousand Oaks, California, USA.
8
Amgen Inc, South San Francisco, California, USA.
9
Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.

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

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