Abstract CT100: Safety and efficacy of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors: First-in-human study
Bibliographic record
Abstract
Abstract Background: GDF15 is overexpressed in solid tumors, with immunosuppressive effects on dendritic cells (DCs), T cells and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. AZD8853 is an IgG1 monoclonal antibody that neutralizes GDF15. This Phase 1/2a, open-label study assessed AZD8853 monotherapy in previously treated advanced/metastatic non-small-cell lung cancer, microsatellite-stable colorectal cancer (MSS-CRC) and urothelial carcinoma (UC) (NCT05397171). Methods: Eligible pts were ≥18 years old with ≥1 measurable lesion per RECIST v1.1 and ECOG PS 0/1. AZD8853 was given IV Q3W until disease progression, unacceptable toxicity or consent withdrawal. The primary objective was safety including dose-limiting toxicities (DLTs). Secondary objectives included efficacy, pharmacokinetics (PK) and pharmacodynamics (PD [free serum GDF15]). Exploratory objectives included peripheral immune PD. Results: During dose escalation, 16 pts (15 MSS-CRC, 1 UC) received AZD8853 (300 mg, n=3; 1000 mg, n=6; 3000 mg, n=7). By June 6, 2023, all pts discontinued treatment and the study. Thirteen pts (81.3%) had treatment-emergent adverse events (TEAEs; Table); the most common were diarrhea (31.3%), abdominal pain (31.3%) and decreased appetite (25%). Eight pts (50%) had Grade ≥3 TEAEs and 6 (37.5%) had serious TEAEs; none treatment-related. There were no DLTs. No pts had responses by RECIST; 5 (31.3%) had stable disease and 11 (68.8%) had disease progression as best response. AZD8853 PK was linear with a half-life of 5-10 days, supporting Q3W dosing. GDF15 suppression was transient. There was no evidence of ctDNA clearance or a dose-dependent change in peripheral immune cells including CD8+ and CD4+ T cells, DCs and MDSCs. Conclusions: AZD8853 was well tolerated. No objective responses or PD effects were seen and GDF15 suppression was not sustained, therefore no further development is planned. TABLE 1. NAND Table. AZD8853 safety AZD8853 300 mg 1000 mg 3000 mg Total Safety, n (%) N=3 N=6 N=7 N=16 TEAEs 3 (100) 4 (66.7) 6 (85.7) 13 (81.3) Grade ≥3 TEAEs 1 (33.3) 3 (50.0) 4 (57.1) 8 (50.0) TRAEs 1 (33.3) 0 2 (28.6) 3 (18.8) Grade ≥3 TRAEs 0 0 0 0 Serious TEAEs 1 (33.3) 3 (50.0) 2 (28.6) 6 (37.5) TEAEs leading to discontinuation of AZD8853 0 1 (16.7)* 0 1 (6.3) TEAEs leading to death 0 1 (16.7)* 0 1 (6.3) DLTs, n (%) N=3 N=6 N=6 † N=15 DLTs 0 0 0 0 *Death due to serious AE of cardiac arrest, unrelated to AZD8853; pt had a history of coronary artery disease, coronary stenting, and pulmonary embolism.†One pt discontinued due to clinical progression prior to completing the DLT evaluation period and was not included in the DLT-evaluable set. DLTs, dose-limiting toxicities; TEAEs, treatment-emergent adverse events, TRAEs, treatment-related adverse events Citation Format: Benedito A. Carneiro, Olumide Gbolahan, Albiruni Abdul Razak, John F. Hilton, Arthur Lambert, John Hood, Michael Pluta, Veronique Bragulat, Elhan Sanai, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. Safety and efficacy of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors: First-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT100.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".