Phase 1b Study Of The MDM2 Antagonist RG7112 In Combination With 2 Doses/Schedules Of Cytarabine
Notice bibliographique
Résumé
Abstract Background Activation of the p53 pathway through inhibition of its negative regulator MDM2 is a promising strategy for cancer therapy. Phase 1 results in AML with RG7112, a small-molecule antagonist of MDM2, demonstrated single-agent activity, including complete responses (CRs) (ASH 2012). Here we report results of a Phase 1b trial of RG7112 in combination with Ara-C in pts with AML. Methods This is a multicenter, open-label phase 1b study of pts with AML treated with escalating oral doses of RG7112 in 2 arms. Arm A: pts unsuitable for standard (re)induction, treated with RG7112 and Ara-C 20 mg/m2 SC both daily × 10 days every 28 days; arm B: relapsed/refractory pts treated with RG7112 × 5 days and Ara-C 1 g/m2 IV × 6 days every 28 days. Primary objectives were to determine MTD and DLTs; secondary objectives were pharmacokinetics (PK), pharmacodynamics, and clinical responses. Blood and bone marrow were collected for PK and biomarker analyses pre- and at multiple on-treatment time points. Mutations in TP53 were detected using the PCR- and microarray-based AmpliChip p53 research test, detecting single-nucleotide alterations of exons 2-11. Pharmacodynamic markers of p53 activation included serum MIC-1 measured by ELISA, and MDM2gene expression by RT-PCR. Results Enrollment is complete with forty-three pts treated (16 arm A, 27 arm B) with escalating doses of RG7112. 3 DLTs included rash and prolonged thrombocytopenia (Arm B) and diarrhea (Arm A). MTD was 1000 mg bid × 10 days (arm A) and 1500 mg bid x 5 days (arm B) based on prolonged cytopenias. PK (Cmax, AUC, and Ctrough) data were comparable with historic monotherapies, suggesting no drug-drug interactions. Adverse events (> 20%) were GI or infectious. Clinical activity Arm A: median age 70 y, median prior therapies 1. During the initial safety period 2 pts died (ARDS, sepsis). See table for results for the 14 pts completing cycle 1. CRs (21%) occurred at 1g and 2g of RG7112 in pts with no prior therapy or HU. ORR (CR,PR, SD/HI) was 43%. Arm B median age 50 y, median prior therapies 3 (all relapsed after Ara-C). During the initial safety period 4 pts died of sepsis (1 complicated by multi-organ failure). See table for results for the 23 pts completing cycle 1. CRs (17%) were observed in patients refractory to DA, and MEC (2) or HiDAc (1) and occurred at RG7112 doses >2g/d. ORR was 52%. Three pts bridged to transplant (1 CR, 2 HI). Abbreviations CRi, complete remission with incomplete recovery; CRp, complete remission with incomplete platelet recovery; PR, Partial Response; SD, Stable Disease; HI, Hematologic Improvement; HU, Hydroxyurea; PD, Progressive Disease; Nl, Normal Karyotype; DA, Daunorubicin and Ara-C; MEC, Mitoxantrone, Etoposide, and Ara-C; HiDAc, High dose intermittent Ara-C; AZA, Azacitidine; MDS, myelodysplastic syndromes. *Two continue on therapy as of July 2013 Biomarker activity MIC-1 induction was similar to RG7112 monotherapy. Preliminary data demonstrated increased MDM2 expression on day 2, consistent with the MoA (p53 activation and associated feedback) previously reported (Ray-Coquard, 2012). TP53 activation did not consistently correlate with clinical activity, implying factors downstream of functional p53 may be critical for activity. Additionally, a predictive mRNA signature that significantly correlates with RG7112 efficacy in cell lines and in phase 1 AML pt samples (Spearman correlation, 0.6; P= 0.0009; manuscript in preparation) was prospectively evaluated in this study. Conclusions Here we report the safety and clinical activity of an MDM2 antagonist in combination with Ara-C in pts with AML. CRs in elderly and heavily pretreated pts refractory to cytarabine-containing regimens were observed. Pharmacodynamic activity of the p53 pathway was demonstrated by increases in MIC-1 and MDM2 expression. Results of ongoing biomarker analyses to predict response for future development will be reported. Disclosures: Yee: Roche: Research Funding. Assouline:Roche: Research Funding. Kasner:Roche: Research Funding. Blotner:Roche: Employment. Jukofsky:Roche: Employment. Middleton:Roche: Employment. Zhi:Roche: Employment. Chen:Roche: Employment. Zhong:Roche: Employment. Nichols:Roche: Employment.
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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».