Safety and clinical activity of MEDI1873, a novel GITR agonist, in advanced solid tumors

Ani S. Balmanoukian, Jeffrey R. Infante, Raid Aljumaily, Aung Naing, Ashish V. Chintakuntlawar, Naiyer A. Rizvi, Helen J. Ross, Michael Gordon, Philip R. Mallinder, Nairouz Elgeioushi, Ignacio Gonzalez-García, Nathan Standifer, Jennifer Cann, Nicholas Durham, Shahram Rahimian, Rakesh Kumar, Crystal S. Denlinger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3þ3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4þ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Original languageEnglish (US)
Pages (from-to)6196-6203
Number of pages8
JournalClinical Cancer Research
Volume26
Issue number23
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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