2674 - A Phase 1 study of MEDI1873, a novel GITR agonist, in advanced solid tumors

Background

MEDI1873 is a novel GITR-ligand/IgG1 agonist fusion protein that binds the co-stimulatory glucocorticoid-induced TNF receptor family-related protein (GITR) on CD4⁺ and CD8⁺ effector T cells and regulatory T cells. This Phase 1 study evaluated safety, maximum tolerated dose (MTD), pharmacokinetics (PK), immunogenicity, immunomodulatory effects and preliminary antitumor activity in pts with advanced solid tumors.

Methods

MEDI1873 was administered IV Q2W. During dose escalation (DE), it was evaluated in 2 single pt cohorts (1.5 and 3 mg), followed by 3 + 3 DE in 6 cohorts (7.5, 25, 75, 250, 500 and 750 mg). Pts with NSCLC, HNSCC or CRC receiving 75 or 250 mg were evaluated in pharmacodynamic (PD) cohorts using biopsies pretreatment and at day 29. All pts had flow cytometric assessment of lymphocytes pre- and on-treatment up to day 43. Antitumor response was assessed using RECIST v 1.1.

Results

As of 1 March 2018, 40 pts were dosed in the DE (28) and PD (12) cohorts. An MTD was not reached (maximum administered dose was 750 mg). Three DLTs occurred: Grade 3 worsening tumor pain at 250 mg, Grade 3 nausea and vomiting at 500 mg and Grade 3 non-STEMI at 750 mg. Any-grade drug-related AEs occurred in 82.5% of pts, most commonly headache (25%) and infusion related reaction (IRR, 20%). Grade 3 drug-related AEs occurred in 22.5% of pts; amylase increase was the only one reported in > 1 pt (n = 2). There were no drug-related Grade 4 or 5 AEs. PK was dose-proportional over a range of 1.5 to 500 mg; elimination half-life was approximately 2 days. Anti-drug antibody incidence was low with minimal PK impact. MEDI1873 engaged GITR on CD4⁺ T cells and increased CD4⁺Ki67⁺ T cells at doses ≥25 mg. Intratumorally, MEDI1873 induced a ≥ 25% decrease in GITR⁺/FOXP3⁺ T cells in 5 of 5 pts with evaluable cells. Immune PD changes were observed in 8 pts who underwent paired biopsies. Best overall response was stable disease (SD) in 42.5% of pts; 17.5% had SD ≥ 24 weeks. Three pts (pancreatic neuroendocrine tumor, lung cancer and mesothelioma) stayed on MEDI1873 for ≥52 weeks without progression.

Conclusions

MEDI1873 has an acceptable safety profile in heavily pretreated pts with solid tumors. PD changes in blood and tumor coupled with prolonged SD in several pts support further clinical exploration of doses ≥250 mg.

Clinical trial identification

NCT02583165, October 22, 2015.

Legal entity responsible for the study

MedImmune.

Funding

MedImmune.

Editorial Acknowledgement

Medical editing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Paul Glacken of Ashfield Healthcare Communications (Macclesfield, UK) and was funded by MedImmune (Gaithersburg, MD, USA).

Disclosure

C.S. Denlinger: Grant: MedImmune, during the conduct of the study; Grants and personal fees: Eli Lilly and Company; Grants: Bristol-Myers Squibb; Personal fees: Merck; Grants: Merrimack Pharmaceuticals; Grants: MedImmune LLC; Personal fees from EMD Serono, Carevive; Grants from Advaxis, Genentech, InCyte Corporation, OncoMed, Astex Pharmaceuticals, Macrogenics, Array Pharmaceuticals, AstraZeneca, outside the submitted work. J.R. Infante: Research funding: Aileron Therapeutics, ARMO BioSciences, AstraZeneca, BioMed Valley Discoveries, Bristol-Myers Squibb, Calithera Biosciences, Calithera Biosciences, Celldex, eFFECTOR Therapeutics, Genentech/Roche, GlaxoSmithKline, Immunocore, Janssen Oncology, MedImmune, Merck, Novartis, Pfizer, Phosplatin Therapeutics, Roche, Roche, Tesaro. A. Naing: Research funding: Amplimmune; ARMO BioSciences; Atterocor; Baxter (I); EMD Serono; Healios; Incyte; Karyopharm Therapeutics; MedImmune; National Cancer Institute; Novartis; Regeneron; Travel, accommodations, expenses: ARMO BioSciences. A. Chintakuntlawar: Principal investigator on clinical investigator initiated trials: Merck and Eisai. N.A. Rizvi: Consulting/Advisory board: Merck, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Pfizer, Lilly, Abbvie, Merck KGaA, Regeneron; Shareholder: Gritstone Oncology, ARMOBiosciences. H. Ross: Research grant funding from AstraZeneca and MedImmune. M. Gordon: Full-time employment: Honor Health; Consultancy: Deciphera. R. Kumar, M. Ma, L. Yan, P. Vicini, N. Standifer, A. Perera, N. Durham. S. Krishnan: Full-time employment: MedImmune. J. Cann: Employee: Medimmune/AstraZeneca. A. Balmanoukian: Speakers' bureau: AstraZeneca, Genentech, BMS, Merck. All other authors have declared no conflicts of interest.