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

21 april 2022 bijgewerkt door: 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.

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

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.

Studietype

Ingrijpend

Inschrijving (Verwacht)

30

Fase

  • Niet toepasbaar

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Locaties

  • China
    • Gansu
      • Lanzhou, Gansu, China, 730000
        • Werving
        • The First Hospital of Lanzhou University
        • Onderonderzoeker:
          • Long Zhao
        • Onderonderzoeker:
          • Haizhen Ma
        • Onderonderzoeker:
          • Juan Cheng, MD
        • Contact:
        • Hoofdonderzoeker:
          • Bei Liu, MD
        • Onderonderzoeker:
          • Jinli Jian
        • Onderonderzoeker:
          • Hao Zhang

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar en ouder (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Enkel

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: 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.
Geneesmiddel: Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
Geneesmiddel: Dasatinib
dasatinib,20mg,po,qd,treatment cycles every 28 days
Actieve vergelijker: 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.
Geneesmiddel: Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
overall survival
Tijdsspanne: 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
Tijdsspanne: 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.

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
mortality
Tijdsspanne: mortality rate at 30 months.
The proportion of patients from enrollment to death was recorded.
mortality rate at 30 months.
recurrence rate
Tijdsspanne: recurrence rate at 30 months.
Record the proportion of patients with recurrence in the study.
recurrence rate at 30 months.
adverse events
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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.
Tijdsspanne: 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
Tijdsspanne: 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.

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

LanZhou University

Medewerkers

Beijing Health Alliance Charitable Foundation

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

13 november 2021

Primaire voltooiing (Verwacht)

1 september 2023

Studie voltooiing (Verwacht)

15 december 2023

Studieregistratiedata

Eerst ingediend

1 september 2021

Eerst ingediend dat voldeed aan de QC-criteria

6 september 2021

Eerst geplaatst (Werkelijk)

13 september 2021

Updates van studierecords

Laatste update geplaatst (Werkelijk)

25 april 2022

Laatste update ingediend die voldeed aan QC-criteria

21 april 2022

Laatst geverifieerd

1 april 2022

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • AZALDDASA3
  • ChiCTR2100042418 (Register-ID: Chinese Clinical Trial Registry)

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Beschrijving IPD-plan

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.

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

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