PB2358: PHASE 1-2 STUDY OF THE SAFETY, PK, PD, AND PRELIMINARY ACTIVITY OF TOLINAPANT IN COMBINATION WITH ORAL DECITABINE/CEDAZURIDINE AND ORAL DECITABINE/CEDAZURIDINE ALONE IN SUBJECTS WITH R/R PTCL
Notice bibliographique
Résumé
Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: There are limited treatment options for patients with Peripheral T-Cell Lymphoma (PTCL) after progression following front line therapy. Tolinapant (ASTX660) is a novel oral non-peptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which also induces necroptosis in T-cell lymphoma models (Ferrari et al., Blood Adv., 2021). An ongoing Phase 1-2 study demonstrates an overall response rate (ORR) of >20% in relapsed/refractory PTCL with single agent tolinapant (Michot et al., EHA 2022). While there are limited studies using decitabine as a hypomethylating agent (HMA) in PTCL, a recent guadecitabine prospective study showed 40% ORR (Wong et al., Leukemia, 2022). Preclinical data demonstrate decitabine treatment leads to re-expression of genes critical for necroptosis and synergy between decitabine and tolinapant in T-cell tumor models (Ward et al. ASH 2021; Manavalan et al. EHA abstract 2022). These data suggest that this combination may have synergistic activity in PTCL. Oral decitabine/cedazuridine (ASTX727) is an oral DNMTi that provides equivalent PK exposure to intravenous decitabine at standard dosing (20 mg/m2 day 1-5 every 28 days). This combination of oral decitabine and cedazuridine was approved in the US, Canada, and Australia for the treatment of intermediate and high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia. There are minimal overlapping toxicities between the study drugs and no expected drug-drug interactions. Aims: The Primary Aim of Phase 1 is to assess safety, and to identify the recommended Phase 2 dose of tolinapant in combination with oral decitabine/cedazuridine. The primary Aim of Phase 2 is to assess preliminary efficacy as determined by overall response rate. Secondary Aims of the trial include assessing safety and to identify the tolerated dosing of oral decitabine/cedazuridine alone in this population and determining the pharmacokinetic parameters of both tolinapant and oral decitabine/cedazuridine. Methods: ASTX660-03 (NCT05403450) is a Phase 1-2, open-label study. To be eligible, subjects with ECOG PS ≤2 must have received at least two prior systemic therapies with evidence of documented progressive disease with at least one measurable lesion by computerized tomography (CT). Subjects with CD30-positive disease must have received or be ineligible for brentuximab vedotin. Key exclusion criteria include ejection fraction <50%, QTc ≥470 milliseconds, and the use of concomitant medications that are either strong or moderate CYP3A4 inhibitors/inducers. There is a lead-in phase to confirm tolerability of the MDS-approved regimen of oral decitabine/cedazuridine in a PTCL population. In Phase 1 subjects are randomized to oral decitabine/cedazuridine alone or to the combination of oral decitabine/cedazuridine with tolinapant. The combination arm will include escalation of tolinapant in dose ranges that have shown efficacy in PTCL. The oral decitabine/cedazuridine only arm will enroll 20-24 subjects. Once the combination arm reaches recommended Phase 2 dose/maximum tolerated dose, there will be a dose expansion of 20 subjects in the combination arm prior to the initiation of the combination dosing in Phase 2 which has an enrollment goal of 102 subjects. There will be no formal statistical analysis in Phase 1. In Phase 2, there will be efficacy analysis for every 34 subjects, without a pause in enrollment. Results: None to date Summary/Conclusion: The Study opened in June 2022 with primary completion estimated to be December 2025. Keywords: Pharmacokinetic, Oral, Peripheral T-cell lymphoma
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) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».