Abstract CT009: Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma
Notice bibliographique
Résumé
Abstract Background: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) is characterized by a consistent coamplification of human double minute 2 homolog (HDM2) and cyclin-dependent kinase 4 (CDK4) which inactivates the tumor suppressor pathways p53 and Rb, respectively. HDM201 is a selective inhibitor of the p53-HDM2 interaction and ribociclib is a CDK4/6 inhibitor. Preclinical studies suggested a synergy in in vitro and in vivo models of WDLPS/DDLPS and both agents have demonstrated single-agent clinical activity in solid tumors. We aim to determine the optimal dose and regimen of HDM201 + ribociclib and to assess the preliminary antitumor activity of this combination in patients (pts) with liposarcoma. Methods: In this multicenter, open-label, Phase Ib ongoing study, pts with locally advanced or metastatic liposarcoma that had unequivocally progressed on, or despite prior systemic therapy were treated orally with HDM201 + ribociclib. Three treatment regimens were explored: Regimen (Reg) 1 (HDM201 + ribociclib daily for the first 2 wks [QD 1st 2 wks] in a 4-wk cycle), Reg 4 (HDM201 every 3 wks + ribociclib QD 1st 2 wks in a 3-wk cycle), and Reg 5 (HDM201 every 4 wks + ribociclib QD 1st 2 wks in a 4-wk cycle). Results: As of Nov 21, 2017, 74 pts received HDM201 + ribociclib (Reg 1 n=26; Reg 4 n=29; Reg 5 n=19); 12 pts (6 each in Reg 4 and 5) were still receiving treatment. Ten pts (Reg 1 n=3; Reg 4 n=6; Reg 5 n=1) discontinued treatment due to adverse events (AEs) and 2 pts (1 each in Reg 4 and 5) died. The most common AE of any grade, regardless of cause, reported across regimens (Reg 1; Reg 4; Reg 5) was nausea (81%; 76%; 63%) which was mainly Grade 1/2 and not dose limiting. Common Grade 3/4 AEs regardless of cause included neutropenia (39%; 52%; 42%), thrombocytopenia (35%; 45%; 42%), anemia (27%; 17%; 21%), leukopenia (27%; 28%; 37%), and lymphopenia (15%; 14%; 21%). Dose-limiting toxicities were reported in 16 pts (2; 9; 5) and all except 1 (prolonged QT) were hematologic (including neutropenia [n=5], thrombocytopenia [n=4], febrile neutropenia, and anemia [n=2 each]). Partial responses were observed in 3 (4%) pts (2 in Reg 4; 1 in Reg 5). Stable disease was achieved by 36 (49%) pts (11 in Reg 1; 16 in Reg 4; 9 in Reg 5). The median progression-free survival (PFS) was 2.7 mo (95% confidence interval [CI]: 1.9-8.2 mo) in Reg 1, 4.8 mo (95% CI: 3.9 mo-not reached) in Reg 4, and 2.1 mo (95% CI: 1.4 mo-not reached) in Reg 5. Conclusions: HDM201 + ribociclib demonstrated a manageable safety profile and preliminary efficacy in pts with locally advanced or metastatic WDLPS/DDLPS, with hematologic toxicities being dose limiting. The median PFS in Reg 4 compares favorably with single-agent CDK4 inhibitors and, alongside a tolerable safety profile, suggests further exploration of this regimen may be warranted in Phase II studies of HDM201 + ribociclib in this patient population. Citation Format: Albiruni Abdul Razak, Sebastian Bauer, Jean-Yves Blay, Richard Quek, Cristina Suárez, Chia-Chi Lin, Marie L. Hütter-Krönke, Ricardo Cubedo, Stephane Ferretti, Christophe Meille, Ensar Halilovic, Giorgia Clementi, Maria Santos-Rosa, Nelson Guerreiro, Astrid Jullion, Claire Fabre, Antoine Italiano. Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT009.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| 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 ».