Comparison of Proteasome Inhibition Activity between Carfilzomib and Bortezomib in the Phase 3 Endeavor Study
Notice bibliographique
Résumé
Introduction: In the randomized phase 3 ENDEAVOR study, treatment with carfilzomib (56 mg/m2) and dexamethasone (Kd56) resulted in a superior progression-free survival (PFS; median 18.7 vs 9.4 months, respectively; hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.44-0.65; one-sided P Methods: Patients in the Kd56 arm received intravenous (IV) carfilzomib as a 30-min infusion on days (D) 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m2 on D1 and 2 of cycle 1 [C1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) was given on D1, 2, 8, 9, 15, 16, 22, and 23. In the Vd arm, bortezomib (1.3 mg/m2; IV or subcutaneous administration) was given on D1, 4, 8, and 11 and dexamethasone (20 mg) was given on D1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Patients in both arms received treatment until withdrawal of consent, progression of disease, or unacceptable toxicity. Population PK and PDn were evaluated as exploratory endpoints. Blood for plasma PK assessments was collected from a subset of 133 Kd56 patients and analyzed by population PK analysis. PDn in the form of proteasome inhibition was measured in whole blood and isolated peripheral blood mononuclear cells (PBMCs) collected from 8 Kd56- and 9 Vd-treated patients at select sites during C1, 2, 3, 5, and 7, using LLVY-AMC as a substrate to measure chymotrypsin-like (CT-L) proteasome activity (Lightcap ES, et al. Clin Chem . 2000;46:673-83). Results: At the 56 mg/m2 dose, carfilzomib was eliminated with a half-life of approximately 1 hr; clearance at 56 mg/m2 was similar to that observed at 27 mg/m2 and 70 mg/m2 and was not impacted by infusion duration (10 min vs 30 min). Treatment with Kd56 resulted in reduction of CT-L activity in whole blood to undetectable levels by 1 hr post-dose on C1D8 (Figure). The extent of proteasome inhibition was greater at all time points for Kd56 vs Vd. Maximal inhibition of the activity of the β5 subunit in whole blood was higher in Kd56-treated pts (100% of C1D1 pre-dose activity) vs Vd-treated pts (74%). Although CT-L activity returned to pre-treatment levels prior to Kd56 dosing on C2D1 and C3D1, activity was reduced to undetectable levels post-dose on these days. Substantial recovery of β5 subunit activity in whole blood was observed in Vd-treated patients at the start of cycles 3, 5, and 7. In contrast, sustained inhibition of >50% was observed in the whole blood of Kd56-treated patients. A limitation of these data is that whole blood is composed primarily of anucleated cells. Prolonged and deeper suppression of proteasome activity by Kd56 compared with Vd demonstrated using whole blood LLVY-AMC methodology was also supported by PBMC assays. Conclusion: Carfilzomib induced a deep and prolonged proteasome inhibition compared with bortezomib. The proteasome inhibition profile of carfilzomib may be consistent with superiority in PFS and OS demonstrated by Kd56 relative to Vd. Figure. Comparison of CT-L proteasome activity between Kd56- and Vd- treated patients in C1, 3, 5, and 7 Disclosures Ludwig: Bristol-Meyers: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Spencer: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kovacsovics: Seattle Genetics: Research Funding; Celgene: Consultancy; Flexus: Research Funding. Minuk: Celgene, Janssen, Amgen, BMS: Other: Personal fees, Research Funding. Kimball: Amgen: Employment, Equity Ownership. Pelham: Amgen Inc.: Employment, Equity Ownership. Ou: Amgen Inc.: Employment, Equity Ownership. Orlowski: BioTheryX: Consultancy, Membership on an entity9s Board of Directors or advisory committees.
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 | 0,005 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,002 |
| 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 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».