A PHASE 1 STUDY EVALUATING PRT2527, A POTENT AND HIGHLY SELECTIVE CDK9 INHIBITOR, IN PATIENTS WITH SELECT RELAPSED/REFRACTORY B‐CELL MALIGNANCIES
Notice bibliographique
Résumé
Introduction: PRT2527 is a potent, highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. CDK9 is a key regulator of transcription elongation and has been studied as a potential target for therapy in transcriptionally addicted cancers, which are dependent on oncogenic drivers with short half-lives. Although most of these drivers do not respond to direct inhibition, studies suggest that a subset of drivers with short half-lives such as MYC, MYB, and MCL1 may be targeted indirectly through CDK9 inhibition in select hematological malignancies and solid tumors. Preclinical data with PRT2527 have demonstrated evidence of on-target inhibition of MYC, MYB, and MCL1, as well as induced apoptosis, as measured by cleaved caspase 3 in cell lines and translational models (e.g., patient-derived xenograft [PDX] models) (Zhang Y et al., AACR-NCI-EORTC 2021). Methods: PRT2527-02 is a phase 1, open-label, multicenter, dose-finding study to evaluate the safety, tolerability, recommended phase 2 dose (R2PD), and preliminary efficacy of PRT2527 in patients with select B-cell malignancies such as aggressive B-cell lymphoma subtypes, mantle cell lymphoma, and chronic lymphocytic lymphoma/small lymphocytic lymphoma (e.g., Richter syndrome). Aggressive B-cell lymphoma subtypes, including diffuse large B-cell lymphoma not otherwise specified, gray zone lymphoma, follicular lymphoma grade 3b, high-grade B-cell lymphoma, and primary mediastinal large B-cell lymphoma or large B-cell lymphoma transformed from indolent B-cell, are eligible to enroll. Patients must have relapsed or be refractory to or ineligible for standard-of-care therapy. Other key eligibility criteria include measurable disease or requirement for treatment in accordance with standard disease-specific criteria for the hematologic malignancies under study, Eastern Cooperative Oncology Group performance status of 0–1, and adequate bone marrow, renal, and liver function. The study consists of dose escalation with successive cohorts of patients receiving escalating doses of intravenous PRT2527 once weekly in a 21-day cycle. PRT2527 treatment will continue until disease progression or unacceptable toxicity, whichever comes first. Dose escalation and de-escalation decisions will be guided by the Bayesian optimal interval design method based on the number of participants with dose-limiting toxicities (DLTs) observed at the dose level under evaluation until a maximum tolerated dose and R2PD have been determined. The primary endpoints include safety, tolerability, DLTs, and RP2D of PRT2527. Secondary endpoints include objective response rate, duration of response, duration of complete response, and pharmacokinetic profile of PRT2527. The study has been open to enrollment since February 2023. Clinical trial information: NCT05665530. The research was funded by: Prelude Therapeutics Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. B. D. Cheson Employment or leadership position: AON, Symbio (Japan) Consultant or advisory role Abbvie, Pharmacyclics, Bristol Myers Squibb, ADC Therapeutics, AstraZeneca, Astellas, Tessa, Imaging Endpoints, Oncopeptides, Ascentage, Reddy Biosimilar Research funding: Lilly, Morphosys, Prelude, GenMab Other remuneration: Expert Testimony: Eagle Therapeutics; Speakers Bureau: BeiGene, Morphosys, Incyte, Lilly F. Morschhauser Consultant or advisory role Roche/Gilead/Novartis/Genmab S. E. Assouline Consultant or advisory role AbbVie, BMS, AstraZeneca, Janssen, BeiGene, Pfizer, Roche Research funding: Novartis Canada 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 Stock ownership: Imago BioSciences Other remuneration: Patents, Royalties: Stanford University C. Sarkozy Consultant or advisory role Janssen, Incyte, GSK, BMS Honoraria: Janssen Research funding: Roche Educational grants: Roche, Incyte
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 | 0,000 | 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 | 0,001 |
| 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 ».