Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
2022年4月21日 更新者：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.
調査の概要
詳細な説明
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.
研究の種類
介入
入学 (予想される)
30
段階
- 適用できない
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究連絡先
- 名前：Long Zhao
- 電話番号：+18919128021
- メール：dragonzhao@126.com
研究場所
-
-
Gansu
-
Lanzhou、Gansu、中国、730000
- 募集
- The First Hospital of Lanzhou University
-
副調査官：
- Long Zhao
-
副調査官：
- Haizhen Ma
-
副調査官：
- Juan Cheng, MD
-
コンタクト：
- Long Zhao
- 電話番号：+18919128021
- メール：zhaodragon@126.com
-
主任研究者：
- Bei Liu, MD
-
副調査官：
- Jinli Jian
-
副調査官：
- Hao Zhang
-
-
参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年歳以上 (大人、高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
Inclusion Criteria:
- Patients with intermediate and high-risk AML who are diagnosed according to the 2016 WHO guidelines, aged ≥18 years;
- Detect minimal residual disease(-) after induction therapy and consolidation therapy;
- Eastern Cooperative Oncology Group (ECOG) performance status score 0-2;
The heart, pulmonary, liver and kidneys have sufficient organ functions:
- Cardiac color doppler ultrasound shows cardiac ejection fraction> 50%, heart function classification NYHA III/IV, no heart block or arrhythmia;
- Patients without severe restrictive/obstructive pulmonary disease;
- 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;
- Renal function: serum creatinine (Cr) < 1.5 times the upper limit of normal.
- The patient and family members agree and sign an informed consent form.
Exclusion Criteria:
- Patients with malignant tumors of other organs;
HCV positive; or HIV positive; or one of the following HBV test results:
- HBsAg positive;
- HBsAg negative, HBcAb positive and HBV DNA titer positive;
- Pregnant and lactating women, and patients who have family planning during the enrollment period;
- Patients considered to be unsuitable for enrollment by the investigator.
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：独身
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：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.
|
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
dasatinib,20mg,po,qd,treatment cycles every 28 days
|
|
アクティブコンパレータ：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.
|
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
overall survival
時間枠：up to 30 months.
|
OS is defined as the time from the date of enrollment until the date of death from any cause.
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up to 30 months.
|
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disease-free survival
時間枠：up to 30 months.
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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.
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
mortality
時間枠：mortality rate at 30 months.
|
The proportion of patients from enrollment to death was recorded.
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mortality rate at 30 months.
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recurrence rate
時間枠：recurrence rate at 30 months.
|
Record the proportion of patients with recurrence in the study.
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recurrence rate at 30 months.
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adverse events
時間枠：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.
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Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
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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.
|
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apoptotic protein and phosphorylated protein
時間枠：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
時間枠：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.
時間枠：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.
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once before enrollment and once after the completion of the study, up to 30 months.
|
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Percentage of bone marrow cell apoptosis population
時間枠：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.
|
協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
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研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (実際)
2021年11月13日
一次修了 (予想される)
2023年9月1日
研究の完了 (予想される)
2023年12月15日
試験登録日
最初に提出
2021年9月1日
QC基準を満たした最初の提出物
2021年9月6日
最初の投稿 (実際)
2021年9月13日
学習記録の更新
投稿された最後の更新 (実際)
2022年4月25日
QC基準を満たした最後の更新が送信されました
2022年4月21日
最終確認日
2022年4月1日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- AZALDDASA3
- ChiCTR2100042418 (レジストリ識別子：Chinese Clinical Trial Registry)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
いいえ
IPD プランの説明
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.
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
いいえ
米国FDA規制機器製品の研究
いいえ
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