A phase I and pharmacokinetic (PK) study of vinorelbine liposomes injection in patients with advanced solid tumors, non-Hodgkin’s lymphoma, and Hodgkin’s disease
Notice bibliographique
Résumé
A150 Introduction: Vinorelbine tartrate injection (VLB) is a cell-cycle specific, lipophilic anti-cancer drug that inhibits mitosis at metaphase through its disruption of microtubule assembly. Alocrest TM (vinorelbine liposomes injection) is a sphingomyelin/cholesterol liposomal (OPTISOME TM ) formulation of VLB (55/45, mol%) that efficiently transports large quantities of drug and prolongs drug release properties in vivo . In a preliminary pharmacokinetic (PK) profile study in ICR mice, Alocrest demonstrated a 68-fold increase in plasma AUC, 29-fold reduction in drug clearance and 265-fold reduction in volume of distribution compared to conventional VLB. The improved PK profile of Alocrest was associated with enhanced anti-tumor activity and therapeutic index in several xenograft models (MX-1, breast; HT-29 colon). This report describes a phase 1 and PK profile study of Alocrest administered to humans as a 60-minute IV infusion on days 1 and 8 every 21 days. Methods: Adult subjects with confirmed solid tumors refractory to standard therapy or for which no standard therapy was known to exist, or relapsed and/or refractory non-Hodgkin’s lymphoma or Hodgkin’s disease and an ECOG PS 0-2 were eligible for enrollment. Safety assessments were described using standard laboratory and clinical dose limiting toxicity (DLT) definitions. Responses were based on RECIST and the Non-Hodgkin’s Lymphoma International Workshop Criteria. PK analyses of total (encapsulated + released) and free (released non-protein bound) VLB were performed on days 1 and 8 and analyzed by LC-MS/MS. Area under the concentration versus time curves from 0 to last (AUC last ) was calculated by noncompartmental analysis. Results: At the time of this report, 13 subjects (M/F: 9/4) with refractory solid tumors (n=11) and non-Hodgkin’s lymphoma (n=2) have been enrolled and received a total of 35 cycles of Alocrest (median 2, range, 1-15) at 4 dose levels (2, 4, 8, and 16 mg/m 2 /dose). The MTD has not yet been reached. The study is currently dosing subjects at 32 mg/m 2 /dose which approximates the approved dose of conventional VLB (30 mg/m 2 /dose). Stable disease was observed in 3 refractory solid tumor subjects (1 each at the 2, 4, and 16 mg/m 2 /dose level) having received a median number of 11 (range, 7-15) cycles of therapy. No DLTs were observed at these dose levels. The mean ± SD total VLB AUC last (ng*h /mL) for Day 1 and 8, respectively, were as follows: 2 mg/m 2 : 7,810 ± 6,030, 4,930 ± 2,740; 4 mg/m 2 : 26,600 ± 9,090, 27,300 ± 12,300; 8 mg/m 2 : 35,400 ± 15,700, 39,600 ± 21,000; 16 mg/m 2 : 68,500 ± 35,200, 65,500 ± 29,800. For free VLB, the mean ± SD AUC last (ng*h /mL) for Day 1 and 8, respectively, were as follows : 2 mg/m 2 : 65.1 ± 31.5, 97.9 ± 66.9; 4 mg/m 2 : 1,140 ± 905, 458 ± 157; 8 mg/m 2 : 378 ± 465, 125 ± 32.3; 16 mg/m 2 : data pending. Conclusions: Alocrest demonstrated acceptable tolerability with encouraging activity in refractory solid tumors over multiple cycles of therapy. There is relatively high inter- and low intra-patient variability in the PK profile of total and free VLB. In plasma, free VLB accounts for a small percentage of the total VLB concentration. It is the extended circulation time of OPTISOME encapsulated VLB that contributes to the hypothesis that Alocrest has the potential to increase tumor drug delivery and improve anti-tumor activity compared to conventional VLB.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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 ».