Treatment of Relapsed or Refractory Lymphoma with the Oral Isotype-Selective Histone Deacetylase Inhibitor MGCD0103: Interim Results from a Phase II Study.
Notice bibliographique
Résumé
Abstract Purpose: MGCD0103 is an oral inhibitor of histone deacetylases (HDACs) with isotype-selective activity against HDAC-1, -2, -3, and -11. MGCD0103 exhibits significant biological activity in preclinical models of hematopoietic cancers. Although several HDAC inhibitors have shown promising clinical activity in patients (pts) with T-cell lymphoid malignancies, the clinical activity of HDAC inhibitors have not been previously examined in B-cell lymphoma. The purpose of this study was to examine the efficacy and tolerability of MGCD0103 as monotherapy for the treatment of relapsed or refractory follicular and diffuse large B-cell lymphoma. Methods : This was an open-label, multi-center, phase II trial in adults (≥18 years) with relapsed or refractory lymphoma. The trial contained 2 cohorts of pts with diagnoses of either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility required the presence of ≥1 site of measurable disease (≥2.0 cm) and an ECOG performance status of 0 or 1. Oral MGCD0103 was initially dosed at 110 mg 3× per week in 4-week cycles, with escalation to 135 mg or reductions to 85 and 60 mg permitted based on patient tolerance. Pts enrolled later in the trial had starting doses of 85 mg, with escalation to 110 mg and reductions to 60 and 40 mg permitted. On day 1 of cycle 1, blood samples were collected for PK analysis before dosing and at 0.5, 1, 2, 4, 6, and 24 hours. Results: To date, 38 pts (mean age, 60.3 ± 13.0 yrs; male, n=18) have been dosed: 19 with DLCBL and 19 with FL, all of whom have received prior Rituxan. Nineteen of 24 pts (79%) who had tumor size reassessed by CT scan after treatment initiation exhibited some tumor reduction; 12 (50%) exhibited >30% reduction and 7 (29%) exhibited >40% reduction. Twenty-five pts (1 pt has not yet had disease reassessed) were formally evaluable for clinical response; 16 (64%) have completed ≥3 cycles (12 weeks) of treatment. A CR was observed in 1 pt with FL after 2 cycles. PRs were observed in 2 pts with DLBCL after 2 and 4 cycles respectively and 1 pt with FL after 6 cycles. Twenty pts required dose reductions for management of toxicities. In 35 pts evaluable for safety, the most common non-hematologic toxicities were fatigue (24 pts), nausea (22), diarrhea (17), anorexia and decreased appetite (12), vomiting (10), and weight loss (9). Grade 3 toxicities occurred in 10 pts; fatigue and weight decrease being the most common. There were no grade 4 non-hematological toxicities. Hematological toxicities were minimal, with 1 pt requiring dose modification for thrombocytopenia and 2 for neutropenia. Significant inhibition of HDAC activity in PBMCs was seen in the majority of pts evaluated. Population PK (N=16) revealed: Cmax 119 ± 73 ng/ml, AUC (0–24) 715 ± 495 ng*hr/ml. Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-cancer activity in relapsed or refractory non-Hodgkin’s lymphoma (DLCBL and FL subtypes) and has a manageable side effect profile.
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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| 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 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 ».