Final Results of Anagrelide Controlled-Release (GALE-401) Safety, Efficacy and Pharmacokinetics in Subjects with Myeloproliferative Neoplasms (MPN)-Related Thrombocytosis
Notice bibliographique
Résumé
Abstract Introduction: Agrylin® (United States) and Xagrid® (European Union) are immediate release (IR) preparations of anagrelide hydrochloride that block megakaryocyte differentiation and proliferation and inhibit the action of cyclic AMP phosphodiesterase. Anagrelide was developed as an inhibitor of platelet aggregation but was found to reduce platelet count at lower doses than the amount needed for platelet aggregation. This led to the development of a controlled release formulation of anagrelide (GALE-401). Early healthy volunteer results demonstrated platelet lowering activity and a pharmacokinetic profile with lower Cmax compared to anagrelide IR. The current study, GALE-401-201, was undertaken in subjects with MPN-related thrombocytosis and the final safety, efficacy, and pharmacokinetics are reported here. Methods: GALE-401-201 is a phase 2 open-label, single arm, clinical proof-of-concept study in chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF) or essential thrombocythemia (ET). Eligible subjects must not be refractory to anagrelide IR and must have a platelet count ≥ 600 K/μL. GALE-401 was administered orally at a starting dose of 0.5 mg twice daily and titrated to a dose that maintained a platelet count of 150-400 K/μL. Platelet response was defined by World Health Organization 2008 (complete response, ≤ 400 K/μL or partial response ≤ 600 k/μL or ≥ 50% reduction from baseline), safety assessments were graded by CTCAE version 4.03, and the pharmacokinetic profile was assessed at the starting dose, weekly sampling during dose titration, and at the final titrated dose using a non-linear mixed effect modeling. Results: Eighteen subjects were enrolled, median age 64 years (range, 40-79), 10 females/8 males, 14 ET, 3 PV, and 1 PV/ET. Three groups of anagrelide subjects were enrolled: naïve, intolerant and tolerant subjects with 10, 5, and 3 subjects, respectively. Baseline mutation of JAK2 V617F was present in 12 (66.7%) subjects, CALR in 3 (16.7%) subjects, and thrombopoietin receptor gene (MPL) in 1 (5.6%) subject. After a median duration of 7 months on GALE-401, an overall response rate of 14 of 18 subjects (77.8%; 7 CRs and 7 PRs) was observed across the anagrelide subject groups with median GALE-401 dose of 2 mg daily (range, 0-5 mg). The median duration of response (CR or PR) is 6.3 months (ongoing) with a median time to first objective response of 3.1 weeks (range, 1.1-5.0 weeks). JAK2 V617F was present at baseline in 7 (38.9%) and CALR mutation 1 (5.6%) of ET subjects who demonstrated a clinical response. Majority of the AEs, regardless of relationship were of Grade 1/2 in severity. Treatment related Grade 3/4 adverse events occurred in 2 subjects; Grade 3 (anemia, pancreatitis, increased creatinine, headache); Grade 4 (cholestatic jaundice). Grade 3/4 events were not correlated with higher anagrelide doses. A logistical regression evaluating the relationship between adverse events severity versus dose, anagrelide maximum plasma concentration (Cmax occurring between the time of the adverse event occurrence and up to 7 days prior) versus adverse events, did not reveal a clear positive correlation. Further exposure-adverse events analyses in addition to pharmacokinetic parameters will be presented. Conclusions: In this pilot clinical proof-of-concept study, GALE-401 produces an overall response rate at a dose comparable to anagrelide IR in a diverse group of subjects both treated and untreated with anagrelide IR. The majority of adverse events were mild to moderate in nature, and the adverse events severity was not correlated with dose or plasma concentration. A comparative controlled study evaluating GALE-401 with anagrelide IR in a well-defined MPN population, such as anagrelide treatment naïve ET, will be further needed to fully elucidate the safety and efficacy profile of GALE-401. Disclosures Troung: Galena Biopharma, Inc.: Research Funding. Saltzman:Galena Biopharma, Inc.: Research Funding. Jawien:Galena Biopharma, Inc.: Research Funding. Lyons:Galena Biopharma, Inc.: Research Funding; Amgen: Consultancy. Berenzon:Galena Biopharma, Inc.: Research Funding. Mena:Galena Biopharma, Inc.: Research Funding. Wingate-Pearse:Galena Biopharma, Inc.: Employment. Barriere:Galena Biopharma, Inc.: Other: Contract Research Organization. Beeson:Galena Biopharma, Inc.: Other: Contract Research Organization. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties: N/A. Choy:Galena Biopharma, Inc.: 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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».