- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05042531
Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
April 21, 2022 updated by: 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.
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Interventional
Enrollment (Anticipated)
30
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Long Zhao
- Phone Number: +18919128021
- Email: dragonzhao@126.com
Study Locations
-
-
Gansu
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Lanzhou, Gansu, China, 730000
- Recruiting
- The First Hospital of Lanzhou University
-
Sub-Investigator:
- Long Zhao
-
Sub-Investigator:
- Haizhen Ma
-
Sub-Investigator:
- Juan Cheng, MD
-
Contact:
- Long Zhao
- Phone Number: +18919128021
- Email: zhaodragon@126.com
-
Principal Investigator:
- Bei Liu, MD
-
Sub-Investigator:
- Jinli Jian
-
Sub-Investigator:
- Hao Zhang
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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
|
Active Comparator: 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
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
overall survival
Time Frame: 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
Time Frame: 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.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
mortality
Time Frame: mortality rate at 30 months.
|
The proportion of patients from enrollment to death was recorded.
|
mortality rate at 30 months.
|
recurrence rate
Time Frame: recurrence rate at 30 months.
|
Record the proportion of patients with recurrence in the study.
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recurrence rate at 30 months.
|
adverse events
Time Frame: 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
Time Frame: 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
Time Frame: 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.
Time Frame: 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
Time Frame: 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.
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Ades L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014 Jun 28;383(9936):2239-52. doi: 10.1016/S0140-6736(13)61901-7. Epub 2014 Mar 21.
- Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, Coutre SE, De Lima M, Fathi AT, Fiorella M, Foran JM, Hall AC, Jacoby M, Lancet J, LeBlanc TW, Mannis G, Marcucci G, Martin MG, Mims A, O'Donnell MR, Olin R, Peker D, Perl A, Pollyea DA, Pratz K, Prebet T, Ravandi F, Shami PJ, Stone RM, Strickland SA, Wieduwilt M, Gregory KM; OCN; Hammond L, Ogba N. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019 Jun 1;17(6):721-749. doi: 10.6004/jnccn.2019.0028.
- Rashidi A, Weisdorf DJ, Bejanyan N. Treatment of relapsed/refractory acute myeloid leukaemia in adults. Br J Haematol. 2018 Apr;181(1):27-37. doi: 10.1111/bjh.15077. Epub 2018 Jan 9.
- Hunault-Berger M, Maillard N, Himberlin C, Recher C, Schmidt-Tanguy A, Choufi B, Bonmati C, Carre M, Couturier MA, Daguindau E, Marolleau JP, Orsini-Piocelle F, Delaunay J, Tavernier E, Lissandre S, Ojeda-Uribe M, Sanhes L, Sutton L, Banos A, Fornecker LM, Bernard M, Bouscary D, Saad A, Puyade M, Rouille V, Luquet I, Bene MC, Hamel JF, Dreyfus F, Ifrah N, Pigneux A. Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial. Blood Cancer J. 2017 Jun 2;7(6):e568. doi: 10.1038/bcj.2017.50. No abstract available.
- Tavor S, Shalit T, Chapal Ilani N, Moskovitz Y, Livnat N, Groner Y, Barr H, Minden MD, Plotnikov A, Deininger MW, Kaushansky N, Shlush LI. Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature. Haematologica. 2020 Dec 1;105(12):2795-2804. doi: 10.3324/haematol.2019.240705.
- Cassileth PA, Harrington DP, Hines JD, Oken MM, Mazza JJ, McGlave P, Bennett JM, O'Connell MJ. Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol. 1988 Apr;6(4):583-7. doi: 10.1200/JCO.1988.6.4.583.
- Molica M, Breccia M, Foa R, Jabbour E, Kadia TM. Maintenance therapy in AML: The past, the present and the future. Am J Hematol. 2019 Nov;94(11):1254-1265. doi: 10.1002/ajh.25620. Epub 2019 Sep 11.
- Shen N, Yan F, Pang J, Zhao N, Gangat N, Wu L, Bode AM, Al-Kali A, Litzow MR, Liu S. Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia. Clin Cancer Res. 2017 Oct 15;23(20):6254-6266. doi: 10.1158/1078-0432.CCR-17-0235. Epub 2017 Jul 18.
- Fernandez S, Desplat V, Villacreces A, Guitart AV, Milpied N, Pigneux A, Vigon I, Pasquet JM, Dumas PY. Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How? Int J Mol Sci. 2019 Jul 12;20(14):3429. doi: 10.3390/ijms20143429.
- Amrein PC. The potential for dasatinib in treating chronic lymphocytic leukemia, acute myeloid leukemia, and myeloproliferative neoplasms. Leuk Lymphoma. 2011 May;52(5):754-63. doi: 10.3109/10428194.2011.555890. Epub 2011 Apr 4.
- Gao X, Lin J, Gao L, Deng A, Lu X, Li Y, Wang L, Yu L. High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia. PLoS One. 2015 Apr 10;10(4):e0124241. doi: 10.1371/journal.pone.0124241. eCollection 2015.
- Xie N, Zhong L, Liu L, Fang Y, Qi X, Cao J, Yang B, He Q, Ying M. Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells. Biochem Pharmacol. 2014 May 1;89(1):74-85. doi: 10.1016/j.bcp.2014.02.019. Epub 2014 Mar 4.
- Al-Jamal HA, Mat Jusoh SA, Hassan R, Johan MF. Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia. BMC Cancer. 2015 Nov 7;15:869. doi: 10.1186/s12885-015-1695-x.
- Sun GK, Tang LJ, Zhou JD, Xu ZJ, Yang L, Yuan Q, Ma JC, Liu XH, Lin J, Qian J, Yao DM. DOK6 promoter methylation serves as a potential biomarker affecting prognosis in de novo acute myeloid leukemia. Cancer Med. 2019 Oct;8(14):6393-6402. doi: 10.1002/cam4.2540. Epub 2019 Sep 4.
- Lang F, Wunderle L, Pfeifer H, Schnittger S, Bug G, Ottmann OG. Dasatinib and Azacitidine Followed by Haploidentical Stem Cell Transplant for Chronic Myeloid Leukemia with Evolving Myelodysplasia: A Case Report and Review of Treatment Options. Am J Case Rep. 2017 Oct 16;18:1099-1109. doi: 10.12659/ajcr.904956.
- La Rosee P, Johnson K, Corbin AS, Stoffregen EP, Moseson EM, Willis S, Mauro MM, Melo JV, Deininger MW, Druker BJ. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines. Blood. 2004 Jan 1;103(1):208-15. doi: 10.1182/blood-2003-04-1074. Epub 2003 Aug 21.
- Guerrouahen BS, Futami M, Vaklavas C, Kanerva J, Whichard ZL, Nwawka K, Blanchard EG, Lee FY, Robinson LJ, Arceci R, Kornblau SM, Wieder E, Cayre YE, Corey SJ. Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. Clin Cancer Res. 2010 Feb 15;16(4):1149-58. doi: 10.1158/1078-0432.CCR-09-2416. Epub 2010 Feb 9.
- Patel AB, Pomicter AD, Yan D, Eiring AM, Antelope O, Schumacher JA, Kelley TW, Tantravahi SK, Kovacsovics TJ, Shami PJ, O'Hare T, Deininger MW. Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms. Leukemia. 2020 Nov;34(11):2981-2991. doi: 10.1038/s41375-020-0858-1. Epub 2020 May 14.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
November 13, 2021
Primary Completion (Anticipated)
September 1, 2023
Study Completion (Anticipated)
December 15, 2023
Study Registration Dates
First Submitted
September 1, 2021
First Submitted That Met QC Criteria
September 6, 2021
First Posted (Actual)
September 13, 2021
Study Record Updates
Last Update Posted (Actual)
April 25, 2022
Last Update Submitted That Met QC Criteria
April 21, 2022
Last Verified
April 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- AZALDDASA3
- ChiCTR2100042418 (Registry Identifier: Chinese Clinical Trial Registry)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
IPD Plan Description
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.
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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