A Phase I Study of ENMD-2076 In Patients with Relapsed or Refractory Leukemia
Notice bibliographique
Résumé
Abstract Abstract 3307 Background: ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase and FLT3, as well as multiple receptor tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and FGFR. A phase I study was conducted to determine the maximum tolerated dose (MTD) and toxicities of ENMD-2076 in patients with refractory hematological malignancies. Methods. Patients (cohorts of 6 evaluable patients per dose level) received escalating doses of ENMD-2076 administered orally daily [225 mg (n=7), 375 mg (n=6), 325 mg (n=9), or 275 mg (n=5)]. Plasma levels of ENMD-2076 were measured on Days 1, 8, & 29 of cycle 1 and at the end of study. Peripheral blood and/or bone marrow were obtained at baseline for ex vivo drug sensitivity testing, and on Days 8 & 29 of cycle 1 for pharmacodynamic (PD) monitoring to assess the effects of ENMD-2076 on cell signaling pathways. The latter flow cytometry-based assay used combined pERK, pAkt, pSTAT5, and pS6 labelling, and tested the effects of acute stimulation with SCF and FLT3 ligands in the presence or absence of pathway inhibitors, including ENMD-2076. Results. Twenty-seven patients have been treated to date (26 AML; 1 CMML-2). Median age is 69 years (range, 43–84 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (89%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens); 2 had received a prior allogeneic stem cell transplant. A total of 42 cycles have been administered, with a median of 1 cycle (range, 0 to 8 cycles); 10 patients (37%) have received 2 or more cycles of therapy. The most common nonhematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Two of 6 patients treated at the 375 mg/day dose level developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue. The dose was therefore decreased to 325 mg/day; one patient on this dose level developed a DLT with grade 3 fatigue. However, as 2 additional patients subsequently developed grade 2 or 3 fatigue (during cycles 1 and 2, respectively), the 325 mg/day dose was not believed to be tolerable for chronic administration in this patient population. The dose was therefore decreased to 275 mg/day; 2 patients subsequently developed DLTs consisting of grade 3 typhilitis and grade 3 syncope, respectively. Overall, no patient experienced grade 4 toxicities or death from ENMD-2076. Of the 20 evaluable patients, one patient achieved a CRi (transfusion-independent with platelets <100 × 109/L), three a morphologic leukemia-free state (MLFS) with a major HI-P and/or HI-E, and 4 other patients had an 11%, 14%, 23%, and 65% reduction in marrow blast count, respectively. Ex vivo studies showed that pre-incubation with ENMD-2076 in concentrations in the range of 0.5–2 mM suppressed growth factor stimulation in the blast cells of most patients tested to date. Decreases in the stimulation of ERK, Akt, STAT5, and S6 were seen in the Day 8 & 29 samples, including a striking inhibition of cell signaling in one patient who achieved a CRi. Conclusions. Single agent ENMD-2076 has activity in a heavily pretreated group of AML patients that may correlate with inhibition of ERK, Akt, STAT5, and S6 activity. The recommended phase two dose (RPTD) is 225 mg/day. Enrollment, as well as PK and PD monitoring of this study, is ongoing. Disclosures: Off Label Use: Clinical trial investigating ENMD-2076 in patients with relapsed or refractory leukemia. Sidor:EntreMed, Inc.: Employment. Fletcher:EntreMed, Inc.: Employment. Arnott:EntreMed, Inc.: Employment. Bray:EntreMed, Inc.: Employment.
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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 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,001 |
| 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 ».