A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adults (rhabdoid tumor cohort) (NCT02601950)
Notice bibliographique
Résumé
Background: Malignant rhabdoid tumors (MRTs), including small cell carcinoma of the ovary hypercalcemic type (SCCOHT) and thoracic sarcoma (TS; distinct, aggressive SMARCA4 negative tumors with rhabdoid features), are highly aggressive with limited response to conventional systemic therapy. Dysfunction of the SWI/SNF complex, due to loss of INI1 or SMARCA4, leads to oncogenic dependence on EZH2 through transcriptional repression caused by aberrant H3K27me3. Tazemetostat, a potent, selective, oral inhibitor of EZH2, demonstrated antitumor activity in both INI1 and SMARCA4-negative preclinical models. Methods: Tazemetostat (800 mg BID) was studied in adults with MRT (confirmed by histology and INI1 loss) in this phase 2 multicenter, open-label, single arm, 2-stage Green-Dahlberg design study. Futility assessment was performed at stage 1 after the first 15 pts completed ≥24-weeks dosing, the final study visit, or terminated early. Success at stage 1 required ≥1 pt achieving a PR or CR. Stage 2 success required confirmed PR or CR in ≥ 5 treated pts. The primary endpoint was overall response rate. Key secondary endpoints included safety/tolerability. Results: With enrollment complete (N = 31; median age of 32 years; 58% female; n = 10 SCCOHT; n = 10 TS; n = 11 other INI1-neg tumors), futility was passed for stage 1, but not for stage 2. There were a total of 2/31 PRs; 1 pt with SCCOHT with a duration of response of 32 weeks and 1 pt with TS with an ongoing response at 8 weeks. Stable disease as best overall response was observed in 7 (23%) pts. Adverse events (AEs) were generally mild. Vomiting (42%), nausea (32%), cancer pain (26%), fatigue (23%), and abdominal pain (23%) were the most frequently reported AEs of any grade. Grade ≥3 AEs, regardless of relationship to study drug, included: death (19%; not treatment-related), anemia (16%), and abdominal pain (10%). No pts discontinued due to treatment-related AEs. Conclusions: Tazemetostat demonstrated clinical activity in 2 difficult to treat tumors (SCCOHT and TS), with generally mild to moderate AEs. Although stage 2 futility was not passed, further understanding of the heterogeneity of these highly aggressive tumors may help to build upon the PR seen in 2 pts. Clinical trial identification: NCT02601950. Editorial acknowledgement: Third-party writing assistance was provided by Katie Crosslin, PhD, and Andrea Eckhart, PhD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), and supported by Epizyme, Inc. Legal entity responsible for the study: Epizyme, Inc. Funding: Epizyme, Inc. Disclosure: R.L. Jones: Consultant: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, PharmaMar. M. Agulnik: Consulting/Advisory: Janssen, Eisai, Novartis, Lilly; Speakers' bureau: Eisai, Bristol-Myers Squibb. R. Chugh: Research funding: Epizyme; Scientific advisor/consultant: Epizyme. O. Mir: Consultancy: Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Eli Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor. Board membership: Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Eli Lilly, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor; Speakers’ bureau: Eli Lilly, Roche, Servie; Stock ownership: Amplitude Surgical, Transgene. Employee: Gustave Roussy. A. Italiano: Advisory board consulting: Epizyme. T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, Aztrazeneca/MedImmune, Lilly, Boehringer Ingelheim, Kadmon, BMS, Polaris, Epizyme. G.D.D. Demetri: Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta, Loxo Oncology, AbbVie, Epizyme, Adaptimmune - Research support to Dana-Farber for GD as PI in clinical trial agreements in DFCI sarcoma unit; Novartis, Pfizer, EMD Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals - consultant/fees; Novartis - patent licensed from Dana-Farber with royalty paid to Dana-Farber; Blueprint Medicines, Merrimack Pharmaceuticals - Member, board of directors, member, scientific advisory board; Blueprint Medicines, Merrimack Pharmaceuticals, G1, Caris Life Sciences, Champions Oncology - consultant advisory board, consulting fees and equity (minor stake, public or non-public); Bessor Pharmaceuticals - consultant, equity (minor stake, non-public) M. Roche, I. Sapir, S. Daigle, A. Clawson: Paid employee and stock with Epizyme. M. Gounder: Paid consultant and board member for Epizyme Medical Advisory Board Karyopharm – advisory board and honorarium Daiichi – advisory board and honorarium TRACON – honorarium Amgen – honorarium. All other authors have declared no conflicts of interest.
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 ».