Abstract CT116: First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors
Authors: Carneiro Benedito A. , Diab Maria , Van Tine Brian A. , Shields Anthony F. , Razak Albiruni Abdul , Hilton John F. , Santana-Davila Rafael , Sanai Elhan , Zeron-Medina Jorge , Bragulat Veronique , Lowery Kath , Lambert Arthur , Hood John , Kumar Rakesh , Jodrell Duncan , LoRusso Patricia 
Published: April 2023

Abstract
Background: The cytokine GDF15 is overexpressed in solid malignant tumors such as colorectal, lung and urothelial cancer, where it modulates T cells, dendritic cells (DCs) and myeloid-derived cells, driving the tumor microenvironment toward an immunosuppressive, tumor-promoting state. AZD8853 is a humanized immunoglobulin G1 monoclonal antibody that binds to, and neutralizes, GDF15. Anti-GDF15 treatment increased T cell proliferation and DC activation, leading to an antitumor immune response in preclinical studies of anti-PD-L1 resistant models. In vitro and in vivo preclinical data support the potential antitumor activity of AZD8853 in pts with selected advanced/metastatic cancers.
Methods: This Phase I/IIa, first-in-human, open-label study (NCT05397171) assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD8853 in pts with histologically or cytologically confirmed locally advanced, unresectable or metastatic mismatch repair-proficient colorectal cancer (pMMR-CRC), non-small-cell lung cancer (NSCLC) and urothelial carcinoma (UC). Up to 165 pts will be enrolled in 3 parts: Part A, dose escalation; Part B, pharmacodynamics expansion; and Part C, efficacy expansion. All pts receive AZD8853 IV. Eligible pts are ≥18 years old with ≥1 measurable target lesion per RECIST v1.1, ECOG PS of 0/1, life expectancy ≥12 weeks and adequate organ and bone marrow function. Pts with NSCLC must have had ≥1 prior line of systemic treatment in the advanced/metastatic setting, and no sensitizing EGFR or ALK aberrations. Pts with pMMR-CRC must have had ≥2 prior treatments in the advanced/metastatic setting. Pts with UC must have had ≥1 prior treatment in the advanced/metastatic setting including platinum-containing therapy and/or a PD-(L)1-inhibitor. Pts with Grade ≥2 unresolved toxicities from prior therapy, symptomatic CNS metastases or leptomeningeal disease, or prespecified active/ongoing infections are excluded. The primary objective is safety, including dose-limiting toxicities, adverse events (AEs), serious AEs and AEs leading to AZD8853 discontinuation. The secondary objectives include assessment of efficacy (objective response rate, disease control rate, duration of response, percentage change from baseline in target lesion size, change from baseline in circulating tumor DNA, and progression-free and overall survival), PK and immunogenicity. Changes in GDF15 serum levels are measured in Parts A and B. Tumoral CD8+ T cell infiltration is measured in a subset of pts from Part B using PET/CT imaging and IHC of paired biopsies. The study is currently recruiting at centers in the USA and Canada with additional sites planned in the UK, France and Spain.
Citation Format: Benedito A. Carneiro, Maria Diab, Brian A. Van Tine, Anthony F. Shields, Albiruni Abdul Razak, John F. Hilton, Rafael Santana-Davila, Elhan Sanai, Jorge Zeron-Medina, Veronique Bragulat, Kath Lowery, Arthur Lambert, John Hood, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT116.