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

AbstractPurpose: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 3+3 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 CD4+ 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.

01 Oct 2018·Annals of Oncology

A phase I study of MEDI1873, a novel GITR agonist, in advanced solid tumors

Article

Author: Durham, N ; Naing, A ; Infante, J R ; Denlinger, C S ; Perera, A ; Gordon, M ; Chintakuntlawar, A ; Balmanoukian, A ; Krishnan, S ; Standifer, N ; Cann, J ; Aljumaily, R ; Ma, M ; Yan, L ; Ross, H ; Rizvi, N A ; Vicini, P ; Kumar, R

04 Mar 2017·OncoImmunologyQ2 · MEDICINE

MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential

Q2 · MEDICINE

ArticleOA

Author: Schwickart, Martin ; Black, Chelsea M. ; Stewart, Ross ; Bamber, Lisa ; Oberst, Michael ; Wilkinson, Robert W. ; Solier, Emilie ; Maguire, Shaun ; Tigue, Natalie J. ; Vaughan, Tristan ; Sridharan, Sudharsan ; Young, Lesley L. ; Chodorge, Matthieu ; Rees, D. Gareth ; Ireland, Samantha ; Perez-Martinez, David ; de Haan, Lolke ; Higazi, Daniel R. ; Yan, Li ; Li, Yi-Ming ; Carter, Edward ; Cann, Jennifer A. ; Andrews, John ; Hair, James ; Jovanović, Jelena ; Springall, Jeremy S. ; Kennedy, Maureen

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD). MEDI1873 was optimized through systematic testing of different trimerization domains, aglycosylation of the GITRL ECD and comparison of different Fc isotypes. MEDI1873 exhibits oligomeric heterogeneity and superiority to an anti-GITR antibody with respect to evoking robust GITR agonism, T-cell activation and clustering of Fc gamma receptors. Further, it recapitulates, in vitro, several aspects of GITR targeting described in mice, including modulation of regulatory T-cell suppression and the ability to increase the CD8⁺:CD4⁺ T-cell ratio via antibody-dependent T-cell cytotoxicity. To support translation into a therapeutic setting, we demonstrate that MEDI1873 is a potent T-cell agonist in vivo in non-human primates, inducing marked enhancement of humoral and T-cell proliferative responses against protein antigen, and demonstrate the presence of GITR- and FoxP3-expressing infiltrating lymphocytes in a range of human tumors. Overall our data provide compelling evidence that MEDI1873 is a novel, potent GITR agonist with the ability to modulate T-cell responses, and suggest that previously described GITR biology in mice may translate to the human setting, reinforcing the potential of targeting the GITR pathway as a therapeutic approach to cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	United Kingdom	MedImmune LLC	15 Jul 2016
Advanced Malignant Solid Neoplasm	Phase 1	United States	MedImmune LLC	09 Nov 2015

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02583165 (Pubmed \| Clin Cancer Res) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	40	MEDI1873	(cxysvzxbnw) = 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) uvkilsltsv (luvpwfieaa ) View more	Positive	01 Dec 2020
NCT02583165 (ESMO2018)	Phase 1	HR-positive/HER2-low Solid Tumors	40	MEDI1873	(jgzayiseyx) = reported in > 1 pt (n = 2) uiyufndnke (qjksewplse ) View more	-	20 Oct 2018

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