PB1887: STING AGONIST FOR THE TREATMENT OF RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA AND HIGH-RISK MYELODYSPLASTIC SYNDROME: A FIRST-IN-CLINIC PHASE 1 STUDY OF GSK3745417
Notice bibliographique
Résumé
Topic: 4. Acute myeloid leukemia - Clinical Background: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are hematologic malignancies originating from immature myeloid progenitor cells within the bone marrow. Depending on age and genetic disposition, approximately 40%-60% of patients may have disease that is refractory to primary treatment, and of those who achieve initial complete response, over 40% will experience relapse. In the relapsed/refractory setting, median survival is inadequate, which highlights an unmet medical need. Within the cGAS-STING-TBK1 pathway, stimulator of interferon genes (STING) is the main adaptor molecule as it modulates the sensing of cytosolic DNA. STING activation mediates the generation of type I interferons (IFNα and IFNβ) and pro-inflammatory cytokines, drivers of T-cell–dependent antitumor immunity. In preclinical studies, STING agonists have also shown direct cytotoxic activity against AML cells in addition to their immune stimulatory activity. Compared with other tumor types, STING is expressed at a higher level in AML cells (The Cancer Genome Atlas, National Cancer Institute), which may explain 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 an appropriate malignancy in which to determine proof of mechanism and investigate the clinical activity of GSK3745417, a novel STING agonist that has so far only been studied in solid tumors. Aims: The primary objectives are to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and cytotoxicity of intravenously administered GSK3745417 in patients with relapsed or refractory AML or high-/very high-risk MDS. Methods: This is a first-in-clinic, phase 1, dose escalation (part 1) and dose expansion (part 2) study. Key eligibility criteria include patients who are 18 to 75 years of age with a diagnosis of relapsed or refractory AML (World Health Organization criteria) or high-/very high-risk MDS (Revised International Prognostic Scoring System) that has relapsed after or was refractory to prior therapy with a hypomethylating agent. Enrolment in part 1 dose escalation is ongoing, which comprises intrapatient dose escalation within cohorts to define a cohort-level maximum tolerated dose. Dosing in part 1 will consist of 3 initial induction cycles of GSK3745417 followed by a maintenance schedule. Part 2 includes an expansion cohort receiving the recommended induction regimen from part 1, followed by maintenance dose escalation. In total, approximately 72 patients will be enrolled: 22 patients in part 1 and 50 patients in part 2. Peripheral blood and bone marrow sampling will permit response assessment and biomarker analysis to elucidate the mechanism of GSK3745417 activity in AML and MDS. Results: Data for the primary endpoint are expected by the end of 2025. Summary/Conclusion: Accrual is ongoing. Clinical trial information: NCT05424380. Keywords: Acute myeloid leukemia, Clinical trial, MDS, MDS/AML
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».