Abstract CT146: AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial
Notice bibliographique
Résumé
Abstract Background Overexpression of pro-survival proteins Bcl-2 and Bcl-xL have been associated with poor prognosis in patients with non-Hodgkin lymphoma (NHL). AZD0466 is a drug-dendrimer conjugate consisting of the dual Bcl-2/Bcl-xL inhibitor AZD4320 covalently conjugated to a pegylated poly-L-lysine dendrimer, which allows for gradual release by hydrolysis. Preclinically, AZD0466 monotherapy has demonstrated efficacy in xenograft models of diffuse large B-cell lymphoma (DLBCL). Here, we report results from a Phase 1 trial (NCT05205161) of AZD0466 in relapsed/refractory (R/R) advanced B-cell NHL (B-NHL). Methods Eligible patients were ≥18 years old and had received 2-5 prior lines of therapy. AZD0466 was administered intravenously, with a dose ramp-up on days 1 and 4 of a 28-day cycle, and weekly administration of the target dose from day 8. The primary objective of the dose escalation phase was to assess the safety and tolerability of AZD0466 in patients with R/R B-NHL and to identify the maximum tolerated dose and recommended phase 2 dose. Preliminary efficacy was evaluated using Lugano 2014 criteria. Secondary objective was evaluation of pharmacokinetic (PK) parameters for the study drug. Results As of November 02, 2023, 7 patients (DLBCL n=5, follicular lymphoma n=1, marginal zone lymphoma (MZL) n=1; median age, 57 [26−79] years) had received AZD0466 at 600 mg (n=3), 1200 mg (n=3), or 2400 mg (n=1). All patients experienced adverse events (AEs). AEs possibly related to AZD0466 were reported in 6 patients, most common: platelet count decrease (57.1%), neutropenia/neutrophil count decrease (42.9%), and hypophosphatemia (28.6%). Grade ≥3 AEs possibly related to AZD0466 were reported in 4 patients: 2 Grade 3 and 1 Grade 4 neutropenia/neutrophil count decrease, and 2 AEs that led to treatment discontinuation (Grade 3 platelet count decrease and dose-limiting Grade 3 troponin increase). Among 6 evaluable patients across all dose levels, 1 patient with MZL treated at 1200 mg had an objective response (partial response). Another 3 patients had a best overall response of stable disease and 2 patients had progressive disease. One patient discontinued the study prior to disease assessment. AZD4320 exposure was dose-proportional, with PK profiles similar to studies with other hematologic malignancies. As a surrogate of Bcl-xL on-target activity, transient thrombocytopenia with moderate platelet count recovery prior to the next dose was observed in most patients, in line with preclinical modeling. Pharmacodynamic modulation based on cleaved caspase-3 induction by AZD0466 was observed at 1200 and 2400 mg. Conclusion AZD0466 ≤1200 mg was clinically well tolerated but evidence of asymptomatic myocardial injury was observed at 2400 mg. The study was terminated due to similar findings in a concurrent trial (D8241C00001; NIMBLE). With an objective response observed at the 1200 mg dose level, further development of agents targeting Bcl-2/xL in NHL is warranted with efforts to reduce the cardiotoxicity profile. Citation Format: Geoffrey Chong, Franck Morschhauser, Alex Herrera, Ki-Seong Eom, Tae Min Kim, Michael Wang, Connor Hall, Fathima Zumla Cader, Kaitlyn Beyfuss, Patricia Cheung, Wei Quan, Shringi Sharma, Yotvat Marmor, Jamal Saeh, Jose Mariz. AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT146.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».