P719: RANDOMIZED PHASE 1-2 STUDY TO ASSESS SAFETY AND EFFICACY OF LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS: INTERIM SAFETY ANALYSIS
Notice bibliographique
Résumé
Background: Cedazuridine (CED), a cytidine deaminase (CDA) inhibitor allows oral availability of decitabine (DEC) and 5 daily doses of the fixed-dose combination of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 days 1-5 (Garcia-Manero et al, 2020). Attenuated HMA regimens (e.g., 3 days of IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017). Aims: This Phase 1/2 study explores the optimal dosing schedule of Low Dose oral DEC/CED in patients with LR-MDS. Methods: A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1 explored 6 different 28-day regimens, ranging from 5-20 mg DEC with 100mg CED and treatment duration of 5-10 days (Figure 1). The primary endpoints were determination of the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLT) and safety. Secondary endpoints included clinical activity based on modified International Working Group (IWG) 2006 MDS response criteria, transfusion independence rate, leukemia-free survival (LFS), and overall survival (OS). In Phase 2, 81 LR-MDS were randomly assigned in a 1:1 ratio to receive the RP2D from Phase 1 or 35 mg DEC/ 100 mg CED (SD) for 3 days, a regimen based on 3-day IV decitabine dosing in the NCCN guidelines for treatment of LR-MDS. Efficacy and safety endpoints of the Phase 2 were the same as those of the Phase 1. Results: In Phase 1, 47 patients were treated with five different DEC/CED regimens. DLT associated with prolonged neutropenia was seen in proportion to the dose per cycle and the number of days of treatment. Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D. The Hematologic Improvement (HI) % for all dosing schedules was 30% (14/47), and the RBC transfusion-independent % over 8 weeks was 33% (7/21). Of the 47 patients treated, 23 (47%) had an event of death at the data cutoff, with a median OS of 31 months (95% Cl: 19, NE); the median LFS was 23 months (95% Cl: 14, 32). In Phase 2, IPSS INT-1 risk was 73% and 65% in the LD and SD arms, respectively. 48% were previously treated for MDS (21% and 26% were treated with ESA or luspatercept, respectively). At baseline, RBC and platelet transfusion dependence was 46% and 14%, respectively. At the data cutoff, 80 subjects had received a median of 4.5 cycles of treatment, and approximately 10 patients had discontinued treatment to receive bone marrowbone marrow transplant. In the pharmacokinetic analysis, the total cycle Area Under Curve (AUC) for decitabine in the LD 5-day was about half of the SD 3-day exposure and 1/4 of the SD 5-day exposure. Reported adverse event terms were similar to those reported for SD 5-day, with the most common grade ≥ 3 treatment-emergent adverse events (TEAEs) being neutropenia (19%), anemia (20%), and febrile neutropenia (6%). Average neutrophil counts by cycle 8 in subjects receiving LD 5-day regimen were slightly higher compared to subjects receiving SD 3-day dosing (Figure 2A), while changes in platelet count were similar in both arms (Figure 2B). Of the 8 all-cause deaths at data cutoff, only 2 and 1 were within 60 and 30 days, respectively, in the SD group. Summary/Conclusion: This Phase 1/2 study shows that a LD 5-day treatment regimen is tolerable and safe with less neutropenia, suggesting that it may be an optimal regimen for LR-MDS provided that longer term efficacy results prove to be comparable to the SD 3-day regimen.Keywords: MDS, Phase I/II, Oral
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 | 0,003 | 0,006 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,003 | 0,000 |
| Bibliométrie | 0,001 | 0,005 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».