Abstract CT146: A phase IB study of the combination of AZD6244 hydrogen sulfate (selumetinib) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC)
Notice bibliographique
Résumé
Abstract Background: Targeting MEK is of great interest in the development of novel agents for treatment of a variety of malignancies. Resistance to MEK inhibitors has delayed the development of novel agents, and better strategies are needed to overcome acquired resistance. Preclinical studies performed at the University of Colorado in KRAS mutant cell lines have shown that several members of the Wnt pathway are overexpressed in cell lines resistant to the MEK inhibitor, selumetinib. Gene set enrichment analysis and synthetic lethal screens demonstrated that genes involved in the canonical and non-canonical Wnt pathways were upregulated in selumetinib-resistant CRC cell lines, whereas the combination of selumetinib and cyclosporin A (CsA), a WNT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial of the combination of selumetinib and CsA. Biomarkers of response to therapy are being co-developed in a preclinical trial of MEK/WNT inhibition in PDX models. We hypothesize that this combination will be safe, potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: This is a dose-escalation phase I trial investigating the combination of selumetinib and CsA in patients with solid tumors with an expansion cohort in patients with mCRC (n = 20). The expansion cohort will utilize a “run-in” of MEK inhibition alone to evaluate adaptive mechanisms of resistance that may identify those patients most likely to respond to the combination. An adaptive statistical design will be used to assess both KRAS/NRAS wild-type and mutant CRC to determine whether either or both subsets should be studied further in phase II trials. Results: As of January 15, 2016, a total of 18 patients have been enrolled and treated with selumetinib and CsA in the escalation phase. One DLT was reported in cohort 1 (G3 hypertension), and three DLTs (G3 hypertension, rash and elevated creatinine) were reported in cohort 2 (n = 12). Grade 1 or 2 nausea (67%) and rash (50%) were reported as the most common AEs. One unconfirmed partial response was noted (CRC KRAS mut), and 9 patients exhibited stable disease as their best response. One patient maintained stable disease for over 9 months. Disease control rate was 56% in the escalation cohort. Preclinical studies are currently being performed using next-generation MEK and WNT inhibitors in CRC PDX models. Conclusions: The combination of selumetinib and CsA is well tolerated with evidence of preliminary anti-tumor activity. Selumetinib at 75mg/kg BID and CsA at 2mg/kg was selected as the recommended phase 2 dose. The dose expansion in patients with metastatic CRC is underway. Preclinical studies and tissue acquisition for correlative studies are ongoing. Citation Format: Anna Capasso, Arvind Dasari, A. Craig Lockhart, Mark Stein, Hanna Sanoff, James Lee, Aaron Hansen, Tanios Bekaii-Saab, Sarah Rippke, James Yao, Funda Meric-Bernstam, S Gail Eckhardt, Christopher h. Lieu. A phase IB study of the combination of AZD6244 hydrogen sulfate (selumetinib) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT146.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 ».