Final results of a first-in-human phase I dose escalation trial of daily oral zelenirstat, a n-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.
Notice bibliographique
Résumé
3082 Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways important in cancer cell biology, including Src and Src family of protein tyrosine kinases. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Zelenirstat is a first-in-class oral small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins. Transcriptomic analysis of zelenirstat treated cell lines identified a myristoylation inhibition sensitivity signature in cancer cells most likely to respond to NMT inhibitor therapy; high sensitivity scores were seen in a range of solid cancers and diffuse large B-cell lymphoma. Based on tumor regression and safety in preclinical models, we hypothesized zelenirstat would be safe to administer and show anticancer activity. Methods: Patients (pts) with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in a multicenter, open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until disease progression or unacceptable toxicity (NCT04836195). The primary endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD). Secondary endpoints were to characterize the pharmacokinetic parameters of zelenirstat and assess anticancer activity. Results: Twenty-nine pts (17 females; 12 males; median age 65 years; median prior systemic treatments 4; 25 advanced solid tumor; 4 R/R B-cell lymphoma) were enrolled and 24 pts were DLT-evaluable. Dose cohorts ranged from 20 mg once daily (OD) to 280 mg OD without DLT until the 280 mg cohort where three DLTs were observed: Gr 3 diarrhea, Gr 3 diverticulitis, and Gr 3 dehydration. MTD and recommended phase 2 dose was established at 210 mg OD. Common adverse events were Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked between 1 and 4 hours across the cohorts with terminal half-lives ranging from 6.7 to 12 hours. Steady state was achieved by Day 8 to 15, and in the higher dose cohorts, trough concentrations exceeded the levels predicted to be therapeutic. Stable disease as best response was seen in 8 (28%) heavily pre-treated pts (3 colorectal, 2 ovarian, 1 pancreatic, 1 appendiceal, and 1 bladder). Progression-free survival, overall survival, and weighted health status were significantly better in pts receiving 210 mg OD compared to those receiving lower doses. Conclusions: Zelenirstat is well-tolerated, reaches plasma concentrations highly active in preclinical models, and shows preliminary signs of encouraging anticancer activity. NMT inhibition represents a new target for ongoing research efforts and further clinical development of zelenirstat is warranted. Clinical trial information: NCT04836195 .
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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 | 0,002 | 0,001 |
| 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 ».