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Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia

21 avril 2022 mis à jour par: Bei Liu, LanZhou University
This project is a prospective, single-center study to evaluate the efficacy, safety and related mechanisms of azacitidine combined with low-dose dasatinib in maintenance therapy in patients with intermediate and high-risk acute myeloid leukemia(AML). The patients were randomly divided into azacitidine group and azacitidine combined with low-dose dasatinib group. The overall survival and disease-free survival were taken as the main end points, and the mortality and recurrence rate were taken as the secondary end points, meanwhile, the incidence of adverse events were evaluated. At the same time, the mRNA expressions of DNA methyltransferase (DNMT1, DNMT3a, DNMT3b), tumor suppressor genes (TP53, P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation genes (pu.1, C/EBP α, C/EBP β) were detected. Pyrophosphate sequencing was used to detect the methylation level of the promoter region of these tumor suppressor genes. Western Blot was used to detect apoptosis proteins (caspase3, caspase8) and phosphorylated proteins (pSTAT3, pSTAT5, pAKT). The proportion of apoptotic population of bone marrow cells was determined by flow cytometry. Therefore, the data in this study will reflect the efficacy and safety of azacitidine or azacitidine combined with low-dose dasatinib in real-world maintenance therapy in patients with medium and high-risk AML.

Aperçu de l'étude

Statut

Recrutement

Les conditions

Intervention / Traitement

Description détaillée

In addition to studying the overall survival, disease-free survival and recurrence rates, mortality and incidence of adverse events of patients treated with azacitidine or azacitidine combined with low-dose dasatinib, we will also study its related mechanisms. One of the pathogenesis of AML is that abnormal DNA methylation makes the cell cycle out of control and carcinogenesis by inhibiting the expression of tumor suppressor genes. In addition, the abnormal activation of tyrosine kinase signal pathway also promotes the development of leukemia. Azacitidine, the hypomethylating agents, can not only inhibit the DNA methyltransferase family, but also activate tumor suppressor genes to inhibit a variety of tyrosine kinase signaling pathways, including JAK-STAT. NaShen et al have directly demonstrated that tyrosine kinase inhibitors (TKIs) can not only inhibit the abnormal activation of tyrosine kinase pathway, but also reduce DNA methylation. This study found that the combination of the second generation TKIs and hypomethylating agents can reduce has a synergistic effect on promoting apoptosis and reducing DNA methylation. In addition, TKIs often produces drug resistance due to long exposure time, and the main mechanisms of drug resistance is due to DNA methylation and abnormal reactivation of tyrosine kinase signal pathway. The combination of TKI and azacitidine reduces DNA methylation and inhibits the reactivation of abnormal tyrosine kinase signal pathway, which is helpful to improve TKI drug resistance. Based on the above theory, we assume that patients treated with azacitidine and dasatinib may have more obvious demethylation effect, increased expression of tumor suppressive genes, more obvious apoptosis, and inhibition of phosphorylated protein expression.So we did the lab tests of these mechanisms.We innovatively used azacitidine and TKIs in the treatment of patients with AML maintenance, in order to reduce drug toxicity, enhance drug efficacy, improve patient prognosis and reduce the financial burden of patients.

Type d'étude

Interventionnel

Inscription (Anticipé)

30

Phase

  • N'est pas applicable

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Coordonnées de l'étude

Lieux d'étude

  • Chine
    • Gansu
      • Lanzhou, Gansu, Chine, 730000
        • Recrutement
        • The First Hospital of Lanzhou University
        • Sous-enquêteur:
          • Long Zhao
        • Sous-enquêteur:
          • Haizhen Ma
        • Sous-enquêteur:
          • Juan Cheng, MD
        • Contact:
        • Chercheur principal:
          • Bei Liu, MD
        • Sous-enquêteur:
          • Jinli Jian
        • Sous-enquêteur:
          • Hao Zhang

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans et plus (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  1. Patients with intermediate and high-risk AML who are diagnosed according to the 2016 WHO guidelines, aged ≥18 years;
  2. Detect minimal residual disease(-) after induction therapy and consolidation therapy;
  3. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2;

  4. The heart, pulmonary, liver and kidneys have sufficient organ functions:

    1. Cardiac color doppler ultrasound shows cardiac ejection fraction> 50%, heart function classification NYHA III/IV, no heart block or arrhythmia;
    2. Patients without severe restrictive/obstructive pulmonary disease;
    3. Liver function: total bilirubin (TBIL) < 2 times the upper limit of normal, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) <2.5 times the upper limit of normal;
    4. Renal function: serum creatinine (Cr) < 1.5 times the upper limit of normal.
  5. The patient and family members agree and sign an informed consent form.

Exclusion Criteria:

  1. Patients with malignant tumors of other organs;

  2. HCV positive; or HIV positive; or one of the following HBV test results:

    1. HBsAg positive;
    2. HBsAg negative, HBcAb positive and HBV DNA titer positive;
  3. Pregnant and lactating women, and patients who have family planning during the enrollment period;
  4. Patients considered to be unsuitable for enrollment by the investigator.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Seul

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: experimental group
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and one group was given azacitidine(75mg/m2, per day on day 1-7]. Dasatinib 100 mg p.o. qd was administered on days 1-28 of each consolidation cycle.
Médicament: Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
Médicament: Dasatinib
dasatinib,20mg,po,qd,treatment cycles every 28 days
Comparateur actif: control group
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and the other group was given azacitidine(75mg/m2, per day on day 1-7)on days 1-28 of each consolidation cycle.
Médicament: Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
overall survival
Délai: up to 30 months.
OS is defined as the time from the date of enrollment until the date of death from any cause.
up to 30 months.
disease-free survival
Délai: up to 30 months.
Event-free survival is defined as the time from enrollment until documented refractory disease, relapse after complete remission(CR) or CR with incomplete recovery of blood counts(CRi), or death from any cause.
up to 30 months.

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
mortality
Délai: mortality rate at 30 months.
The proportion of patients from enrollment to death was recorded.
mortality rate at 30 months.
recurrence rate
Délai: recurrence rate at 30 months.
Record the proportion of patients with recurrence in the study.
recurrence rate at 30 months.
adverse events
Délai: Adverse events were assessed weekly during the first and second cycles, and every two cycles thereafter (each cycle is 28 days), up to 30 months.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Adverse events were assessed weekly during the first and second cycles, and every two cycles thereafter (each cycle is 28 days), up to 30 months.
apoptotic protein and phosphorylated protein
Délai: once before enrollment and once after the completion of the study, up to 30 months.
The relative expression of apoptotic protein(caspase3, caspase8) and phosphorylated protein(pSTAT3, pSTAT5, pAKT) were detected by western blot with bone marrow aspirate.
once before enrollment and once after the completion of the study, up to 30 months.
DNA methyltransferase, tumor suppressor genes and differentiation genes
Délai: once before enrollment and once after the completion of the study, up to 30 months.
To detect the mRNA expression of DNA methyltransferase(DNMT1, DNMT3a, DNMT3b), tumor suppressor genes(TP53,P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation gene(pu.1, C/EBPα, C/EBPβ) with bone marrow aspirate by Q-PCR.
once before enrollment and once after the completion of the study, up to 30 months.
methylation level in the promoter region of some tumor suppressor genes.
Délai: once before enrollment and once after the completion of the study, up to 30 months.
Detection of methylation level in the promoter region of the above tumor suppressor genes by pyrophosphate sequencing using patient bone marrow aspirate.
once before enrollment and once after the completion of the study, up to 30 months.
Percentage of bone marrow cell apoptosis population
Délai: once before enrollment and once after the completion of the study, up to 30 months.
The percentage of apoptotic population of bone marrow cells was determined by flow cytometry.
once before enrollment and once after the completion of the study, up to 30 months.

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

LanZhou University

Collaborateurs

Beijing Health Alliance Charitable Foundation

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

13 novembre 2021

Achèvement primaire (Anticipé)

1 septembre 2023

Achèvement de l'étude (Anticipé)

15 décembre 2023

Dates d'inscription aux études

Première soumission

1 septembre 2021

Première soumission répondant aux critères de contrôle qualité

6 septembre 2021

Première publication (Réel)

13 septembre 2021

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

25 avril 2022

Dernière mise à jour soumise répondant aux critères de contrôle qualité

21 avril 2022

Dernière vérification

1 avril 2022

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • AZALDDASA3
  • ChiCTR2100042418 (Identificateur de registre: Chinese Clinical Trial Registry)

Plan pour les données individuelles des participants (IPD)

Prévoyez-vous de partager les données individuelles des participants (DPI) ?

NON

Description du régime IPD

After the completion of the clinical trial, we will choose whether to disclose the result according to the relevant regulations of the Chinese Genetic Office.

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Non

Étudie un produit d'appareil réglementé par la FDA américaine

Non

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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