Results of a phase I dose escalation and expansion study of tegavivint (BC2059), a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumor.
Notice bibliographique
Résumé
11523 Background: Desmoid tumors are known to have increased nuclear β-catenin levels. Tegavivint selectively disrupts the interaction of β-catenin and TBL1/ TBLR1, resulting in specific degradation of nuclear β-catenin. The primary objectives of this study were to determine the maximum tolerated dose (MTD), safety, and preliminary efficacy of tegavivint in patients (pts) with desmoid tumors. Methods: This study ( NCT03459469) utilized an accelerated dose escalation schema for the first two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D) of tegavivint, followed by a dose expansion phase. The study included adult pts with sporadic desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery, or symptomatic), unresectable, and measurable via WHO criteria. Tegavivint was administered IV weekly (three weeks on, one week off) up to two years. Results: 24 pts were enrolled. Dose escalation enrolled 17 pts in six dose levels from 0.5 - 5 mg/kg. In dose expansion, 7 additional pts were enrolled. Dose expansion cohort also included 6 pts in dose escalation that were escalated to RP2D and 3 pts treated at RP2D in dose escalation (n = 16 total). Median age was 43 years (18-66). Median time from diagnosis was 3.1 years with median of one prior systemic treatment (range 0-6). Median time on study was 9.4 months; 3 pts remain on study at data cut-off. No dose-limiting toxicities were observed; MTD was not determined. RP2D was declared at 5 mg/kg based on pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (C min ) exceeded in vitro IC 50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts included fatigue (71%), headache (38%), nausea (33%), constipation (21%), decreased appetite (21%), and dysgeusia (21%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, increased ALT, diarrhea, and headache occurred in 5 separate pts. There were no grade 4-5 adverse events (AEs). One serious AE of Grade 2 extravasation occurred. Objective response rate (ORR) of 17% across all dose levels and 25% at RP2D (WHO and RECIST criteria) were observed. Median duration of response was 8.1 months (range 6 to 11.8 months) with all responses ongoing. The 9-month progression free survival rate was 76% (95% CI: 54 - 90%) among all pts and 79% (95% CI: 51 – 93%) among those treated at RP2D. Patient reported outcomes and correlative science will be included in the presentation. Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 AEs and no serious toxicity associated with WNT inhibition. The ORR of 25% at the RP2D warrants continued development of tegavivint in desmoid tumors. Clinical trial information: NCT03459469.
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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 | 0,003 | 0,007 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 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 | 0,001 |
| 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 ».