Abstract A082: A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML
Notice bibliographique
Résumé
Abstract Background: Activation of the p53 pathway by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy. We previously reported the phase 1 results in solid tumor patients (pts) of RO6839921, a small-molecule pegylated IV prodrug of the MDM2 antagonist idasanutlin (active principle = AP), which was developed with the goal of reducing exposure variability to improve the therapeutic index. We report here on the safety, PK, PD, and activity in AML pts. Methods: This was an open-label phase I monotherapy study evaluating RO6839921 in R/R AML pts on a 5-day dosing schedule. Primary objectives were to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD, DLT rate ≤ 33%). Secondary objectives were to assess PK, PD, and preliminary activity. Maximum escalation increments followed a Modified Fibonacci sequence. TP53 mutational status was assessed by next-generation sequencing from bone marrow samples. Serum MIC-1 (macrophage inhibitory cytokine-1), a p53 transcriptional target, was analyzed by Elecsys® ECL as a PD marker of p53 activation. Results: 26 DLT-evaluable pts were treated at doses between 120-300 mg AP. The MTD was 250 mg with DLTs reported at 250 mg (2/8 pts, 25%) and 300 mg (2/5 pts, 40%) (table). Related AEs ≥ G3 in >5% of pts included febrile neutropenia (3/26, 11.5%), epistaxis and platelet count decreased (both 2/26, 7.7%). Related AEs of all grades observed in > 20% pts were diarrhea, nausea, vomiting, decreased appetite, and fatigue. PK analyses showed rapid and near-complete conversion of prodrug to AP and dose-proportional exposure across the doses tested (table). Variability ranged from 30-47% (22-54% for idasanutlin). 11/26 pts had evidence of antileukemic activity (CR, CRi/MLFS, PR, HI/SD) for a disease control rate of 42%, with a composite CR rate of 7.7% (1 CR, 1 CRi/MLFS; 2/26); TP53 was evaluable in 24 pts; 21 (87.5%) were wild type and 3 mutant (12.5%). 10/11 pts with activity were wild type and 1 did not have a sample. p53 activation was demonstrated by MIC-1 induction in serum and was associated with AP exposure. Conclusions: RO6839921 shows a PK profile similar to idasanutlin. The MTD of 250 mg AP qd x 5 days has a manageable safety profile in R/R AML at ~25% of the idasanutlin dose identified for development in this population. Single-agent antileukemic activity is observed in 42% pts overall, including 4 of 8 pts (50%) at the MTD. NCT02098967. Arm B Cohort(n)Dose(mg AP)Prior AML induction regimens (median and range)ELN risk at initial diagnosis (Favorable, Int-1, Int-2, Adverse)TP53 status (Wild Type, Mutant, or Not Evaluable)PK (AP on D5)DLT eventsAnti-leukemicactivity*FI-1I-2AdvCmax (µg/ml)AUC0-24 (hr*µg/ml)Cohort 1 (n = 6)1202 (0-4)00155 WT, 1 NE18 ± 690 ± 30none2 HI/SDCohort 2 (n = 7)2001 (1-4)13215 WT / 1 MT / 1 NE32 ± 3164 ± 41none1 PR, 2 HI/SDCohort 3 (n = 5)3002 (0-3)01133 WT / 2 MT42 ± 8335 ± 93G4 QTcF prolongation, G3 colitis1 CRi/MLFS, 1 HI/SDCohort 4MTD(n = 8)2501 (0-2)13138 WT43 ± 9 (n=3)278 ± 72 (n=3)G3 stomatitis, G3 diarrhea1 CR, 1 PR, 2 HI/SDTotal(n = 26)11 (42%) Citation Format: Karen Yee, Geoffrey Uy, Sarit Assouline, Carolyn D. Britten, Jianguo Zhi, Steven Blotner, William Pierceall, Brian Higgins, Lin-Chi Chen. A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A082.
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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».