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

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

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Biomarkers
  • Cell Line, Tumor
  • Female
  • Glucocorticoid-Induced TNFR-Related Protein / agonists*
  • Glucocorticoids / pharmacology*
  • Humans
  • Immunophenotyping
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / diagnostic imaging
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phenotype

Substances

  • Antineoplastic Agents, Immunological
  • Biomarkers
  • Glucocorticoid-Induced TNFR-Related Protein
  • Glucocorticoids
  • TNFRSF18 protein, human

Associated data

  • ClinicalTrials.gov/NCT02437916