PHASE 1 STUDY OF PRT1419 (MCL1 INHIBITOR) AS MONOTHERAPY OR IN COMBINATION WITH AZACITIDINE OR VENETOCLAX IN PATIENTS WITH RELAPSED/REFRACTORY MYELOID OR B‐CELL MALIGNANCIES
Notice bibliographique
Résumé
Introduction: PRT1419 is a potent and selective inhibitor of myeloid cell leukemia-1 (MCL-1). MCL-1 is frequently amplified or overexpressed in hematologic malignancies and is associated with higher grade malignancy and poor prognosis (Xiang et al., Onco Targets Ther 2018). Azacitidine (AZA) treatment was shown to induce several proapoptotic changes in primary acute myeloid leukemia (AML) isolates, including a decrease in MCL-1 protein levels (Tsao et al, Ann Hematol 2012; Jin et al, Clin Cancer Res 2020). Several mechanisms of primary and acquired resistance have been described in patients (pts) with AML treated with venetoclax (VEN)-based regimens, including the loss of dependence on BCL-2 and upregulation of MCL-1 (Saliba et al., Cancer Drug Resist 2021; Pei et al., Cancer Discov 2020). Considering that MCL-1 upregulation is a mediator of VEN resistance and AZA downregulates MCL-1, PRT1419 may confer additive or synergistic benefits to AZA or VEN in treatment-resistant myeloid or B-cell malignancies. Methods: PRT1419-03 is a phase 1, open-label, multicenter, dose-finding study to evaluate the safety, tolerability, recommended phase 2 dose (R2PD), and preliminary efficacy of PRT1419 as monotherapy or in combination with AZA or VEN in pts with selected relapsed/refractory myeloid or B-cell malignancies. Pts must have progressed on prior treatment without access to, or eligibility for, further approved therapies. Adult pts with confirmed diagnosis of AML, CMML, MDS, MDS/MPN Overlap Syndrome, CLL/SLL, or B-cell NHLs (mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma) are eligible for this study. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ and cardiac function as assessed by echocardiogram or biochemical markers of cardiac damage. As monotherapy, pts will receive escalating doses of intravenous PRT1419 once weekly in a 28-day cycle using a 3 + 3 dose escalation design until a maximum tolerated dose (MTD) or RP2D dose has been reached. Once the RP2D for monotherapy has been defined, pts will receive escalating doses of PRT1419 in combination with AZA (myeloid malignancies) or VEN (myeloid malignancies; B-cell malignancies) until MTD/RP2D is reached. Pts will then be enrolled into indication-specific dose confirmation cohorts. PRT1419 treatment will continue until relapse/disease progression, intolerance, or pt withdrawal. The primary endpoints include safety, tolerability, dose-limiting toxicities (DLTs), and RP2D of PRT1419 as monotherapy. Secondary endpoints include safety, tolerability, DLTs, RP2D for PRT1419 in combination The research was funded by: Prelude Therapeutics Keywords: combination therapies, molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. R. R. Zuniga Employment or leadership position: New York Cancer & Blood Specialist - Port Jefferson Station, NY Consultant or advisory role Mirati G. Keiffer Consultant or advisory role Astellas Honoraria: Astellas Research funding: AbbVie, Prelude Therapeutics, Cyteir Therapeutics F. Ravandi-Kashani Consultant or advisory role BMS/celgene, Novartis, Astellas, Abbvie, Jazz, Taiho, Syros Honoraria: BMS/celgene, Novartis, Astellas, Abbvie, Jazz, Taiho, Syros Research funding: Amgen, Abbvie, Astex, Prelude, Biomea A. D. Goldberg Consultant or advisory role AbbVie, Daiichi Sankyo, Astellas, and Genentech Honoraria: Dava Oncology Research funding: AbbVie, Aptose, Daiichi Sankyo, Celularity, ADC Therapeutics, Aprea, AROG, Pfizer, Prelude, and Trillium E. Traer Consultant or advisory role Abbvie, Astellas, Daiichi-Sankyo, Servier Research funding: Prelude Therapeutics, Schrodinger, Incyte, Astra-Zeneca Other remuneration: Patents, Royalties: Humarrow, Inc L. P. Frenzel Consultant or advisory role Abbvie Educational grants: Abbvie C. Röllig Consultant or advisory role AbbVie, Astellas, BMS, Jazz, Novartis, Pfizer, Servier Honoraria: AbbVie, Astellas, BMS, Jazz, Novartis, Pfizer, Servier Research funding: AbbVie, Novartis, Pfizer W. Sun Honoraria: Prelude S. K. Atwal Employment or leadership position: Prelude Therapeutics Stock ownership: Prelude Therapeutics W. Hong Employment or leadership position: Prelude Therapeutics, Imago BioSciences, Genentech Consultant or advisory role Imago BioSciences Stock ownership: Imago BioSciences Other remuneration: Patents, Royalties: Stanford University S. E. Assouline Consultant or advisory role AbbVie, BMS, AstraZeneca, Janssen, BeiGene, Pfizer, Roche Research funding: Novartis Canada
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| 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 | 0,001 |
| 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 ».