Abstract CT147: Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors
Notice bibliographique
Résumé
Abstract AZD1208 is a potent oral ATP-competitive, pan-PIM kinase inhibitor. Here we report the results of 2 Phase 1, open-label, multi-center dose escalation studies, recruiting patients with recurrent or refractory AML or advanced solid tumors including malignant lymphoma. The studies examined the safety, tolerability, pharmacokinetics and preliminary efficacy of AZD1208 in patients including evaluation of pharmacodynamic biomarkers in the AML study. The AML study was a first-in-patient study where 32 patients were treated and the range of treatment duration ranged from 15 to 27 days. In patients with heavily treated AML, AZD1208 was generally well tolerated up to doses of 700 mg QD, but was not tolerated at the 900 mg dose. The most common AEs reported likely to be associated with AZD1208 were nausea (37.5%), diarrhea (21.9%), vomiting (18.8%) and fatigue (18.8%). Three DLTs were reported including 1 case of Guillain-Barré syndrome at the 700mg dose and 2 cases of rash at the 900mg dose. Although there were no AML responses to AZD1208 treatment, reductions in peripheral blasts were seen in 5 patients. Modulation of PIM mediated biomarkers was observed with a greater than 50% reduction in pBAD in 14 out of 20 patients and a reduction in p4EBP1 in 6 out of 14 patients. There was no correlation of biomarker modulation and peripheral blast reduction. The solid tumor study recruited 35 patients with a median treatment duration of 41 days (range of 10-357 days). The best objective response was stable disease. Similar AEs to those seen in the AML study were observed in the solid tumor study. DLTs were reported in 4 patients including 2 patients with fatigue (800mg), increased GGT (240mg) and vomiting (540mg). In this study, AZD1208 was well tolerated as monotherapy at doses up to 700 mg QD, but was not tolerated at 800 mg QD. The MTD of AZD1208 was not determined in either study due to termination of development, however was below 900 mg in the AML study and below 800 mg in the solid tumor study. The PK of AZD1208 in both studies showed similar characteristics and was highly variable and generally dose proportional across the range of 120 mg to 900 mg. In the solid tumor study the absorption following multiple dosing was rapid, exposure showed time-dependent PK and interestingly, the accumulation ratios of exposure decreased with increasing doses. One possible mechanism for the decreased exposure is through increased CYP3A4 activity, demonstrated from a 4β-hydroxycholesterol assay showing that AZD1208 increased CYP3A4 activity after continuous dosing resulting in increased clearance of AZD1208 and perhaps resulting in decreased clinical activity. Overall, AZD1208 was generally well tolerated; however, there was no clear evidence of anti-tumor activity from AZD1208 monotherapy treatment. Citation Format: Jorge Cortes, Kenji Tamura, Daniel J. DeAngelo, Johann de Bono, David Lorente, Mark Minden, Geoffrey L. Uy, Hagop Kantarjian, Karen Keating, Kristen McEachern, Karthick Vishwanathan, Robert E. Godin, Janet Elizabeth Pease, Emma Dean. Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors. [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 CT147.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».