First-in-Human Study to Evaluate the Safety and Efficacy of Anti-GDF15 Antibody AZD8853 in Patients with Advanced/Metastatic Solid Tumors
Bibliographic record
Abstract
PURPOSE: Growth and differentiation factor 15 (GDF15) is overexpressed in multiple solid tumors and is thought to exert immunosuppressive effects in the tumor microenvironment. AZD8853 is an anti-GDF15 mAb. PATIENTS AND METHODS: This first-in-human, phase I/IIa, open-label study (NCT05397171) assessed AZD8853 monotherapy in previously treated patients with advanced/metastatic microsatellite-stable colorectal cancer and urothelial carcinoma. The primary objective was safety including dose-limiting toxicities. Secondary objectives included efficacy, pharmacokinetics, and pharmacodynamics (PD), including free serum GDF15. Exploratory objectives included biomarkers of clinical activity and effects on cancer cachexia. RESULTS: During dose escalation, 16 patients received AZD8853 300 mg (n = 3), 1,000 mg (n = 6), or 3,000 mg (n = 7) intravenously every 3 weeks; 15 patients had microsatellite-stable colorectal cancer; and one patient had urothelial carcinoma. By June 6, 2023, all patients had discontinued treatment. Thirteen (81.3%) patients had treatment-emergent adverse events (TEAE); most commonly diarrhea (31.3%), abdominal pain (31.3%), and decreased appetite (25%). Eight (50.0%) patients had grade ≥3 TEAEs, and six (37.5%) had serious TEAEs, none treatment related. There were no dose-limiting toxicities. The best response per RECIST v1.1 was stable disease in five (31.3%) patients and disease progression in 11 (68.8%) patients. AZD8853 showed linear pharmacokinetics with a half-life of 5 to 10 days, supporting every 3 weeks dosing. AZD8853 suppression of GDF15 was transient. There was no evidence of ctDNA clearance or dose-dependent changes in peripheral T cells. Changes in body weight showed no apparent trends. CONCLUSIONS: AZD8853 was well tolerated; however, no objective responses or PD effects were seen, and GDF15 suppression was not sustained. The study was terminated after dose escalation. SIGNIFICANCE: GDF15 is upregulated in the tumor microenvironment and suppresses antitumor immune responses. In this first-in-human trial, the anti-GDF15 antibody AZD8853 was well tolerated in previously treated patients with advanced/metastatic solid tumors, but no objective responses or PD effects were seen and GDF15 suppression was not sustained.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".