Abstract CT038: A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma
Notice bibliographique
Résumé
Abstract Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include histones and proteins involved in signal transduction, gene transcription, DNA repair, and mRNA splicing. PRMT5 overexpression occurs in a number of different cancers, and higher expression is correlated with poor prognosis. Additional published data implicates PRMT5 in tumorigenesis, and as such it represents a novel target for therapeutic intervention in oncology. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent antitumor activity in vivo in animal models. Methods Study 204653 is a Phase I, two-part, open-label, dose escalation/expansion study assessing the safety and tolerability of GSK3326595 in adult subjects with relapsed/refractory solid tumors and non-Hodgkin’s lymphoma. Dose escalation is being performed in subjects with solid tumors of any histology. An accelerated dose titration is employed with one subject per dose level until the occurrence of a ≥ Grade 2 non-disease related toxicity. Thereafter, subjects are enrolled in cohorts of approximately 3, and a modified toxicity probability interval (mTPI) method is used to guide dose escalation decisions. Dose escalation continues until the maximum tolerated dose (MTD) is identified. All data, including safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity, will be used to identify a recommended Phase 2 dose (RP2D). In Part 1, approximately 42 subjects are to be enrolled (30 subjects in dose escalation and an additional 12 subjects at or about the MTD to collect additional data, including PD and metabolites); no hypothesis will be tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK3326595 will be evaluated in expansion cohorts of subjects with select tumor types. Based on preclinical data, enrollment is initially limited to subjects with triple-negative breast cancer (TNBC), metastatic bladder cancer (mBC), glioblastoma multiforme (GBM), and non-Hodgkin’s lymphoma (NHL); additional cohorts may be added based on emerging preclinical and clinical data. Two cohorts of NHL are scheduled, allocated by TP53 wild type versus mutant status. Up to 138 subjects may be enrolled in Part 2, and cohorts may be closed early for futility. As of 17 January 2017, recruitment is ongoing across four centers (USA, Canada, Netherlands, and France), and four subjects have been enrolled into the dose-escalation cohorts. ClinicalTrials.gov identifier: NCT02783300 Study is funded by GlaxoSmithKline Citation Format: Drew Rasco, Anthony Tolcher, Lillian L. Siu, Kimberley Heinhuis, Sophie Postel-Vinay, Olena Barbash, Jacqueline L. Egger, Shelby Gorman, Thierry Horner, Arindam Dhar, Brandon E. Kremer. A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT038. doi:10.1158/1538-7445.AM2017-CT038
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 | 0,002 | 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 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| 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 ».