Abstract CT124: A first-in-clinic phase 1 study of GSK3745417 STING agonist in relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome
Bibliographic record
Abstract
Abstract Background: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are hematologic malignancies arising from immature myeloid progenitor cells in bone marrow. Depending on age and genetic disposition, as many as 40% to 60% of patients may have disease that is refractory to primary treatment, and of those who achieve initial complete response, more than 40% will experience relapse. In the relapsed/refractory setting, median survival is limited and therefore represents an unmet medical need. Stimulator of interferon genes (STING) is the key adaptor molecule in the cGAS-STING-TBK1 pathway, which mediates the sensing of cytosolic DNA, and its activation generates type I interferons (IFNα and IFNβ) and pro-inflammatory cytokines instigating T-cell-dependent antitumor immunity. In addition to their immune stimulatory activity, STING agonists have demonstrated direct cytotoxic activity against AML cells in preclinical studies. STING is expressed at a higher level in AML cells than in other tumor types (The Cancer Genome Atlas, National Cancer Institute), which may lead to the observed cytotoxicity upon STING activation (Gulen MF, et al. Nat Commun 2017.8:427). The high level of STING expression combined with preclinical evidence of antitumor activity makes AML a suitable indication in which to establish proof of mechanism and evaluate the clinical activity of GSK3745417, a novel STING agonist that has so far only been studied in solid tumors. Methods: This phase 1 study (NCT05424380) will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and cytotoxicity of GSK3745417 administered as an intravenous infusion. Eligible patients will be 18 to 75 years of age with a diagnosis of relapsed or refractory AML (World Health Organization criteria) or high-/very high-risk MDS by (Revised International Prognostic Scoring System) that has relapsed after or been refractory to prior therapy with a hypomethylating agent. Patients are currently being enrolled in part 1 dose escalation, which incorporates intrapatient dose escalation within cohorts, to determine a cohort-level maximum tolerated dose. Dosing in part 1 will include 3 initial induction cycles of GSK3745417 followed by a maintenance schedule. Part 2 involves an expansion cohort receiving the recommended induction regimen from part 1, followed by Montesinos, et al. AACR 2023maintenance dose escalation. Approximately 72 patients will be enrolled: approximately 22 patients in part 1 and 50 patients in part 2. Peripheral blood and bone marrow sampling will allow response assessment and biomarker analysis to understand the mechanism of GSK3745417 activity in AML and MDS. Citation Format: Pau Montesinos, Haifa Al-Ali, Juan M. Alonso-Dominguez, Madlen Jentzsch, Mojca Jongen-Lavrencic, Maria Paola Martelli, Christoph Röllig, Simona Sica, Riham Iadevaia, Kaitlin Yablonski, Tianli Wang, Zafar Mahmood, Giedre Koenen, Hank Schmidt, Jingsong Yang, Karen Yee. A first-in-clinic phase 1 study of GSK3745417 STING agonist in relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome [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 CT124.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".