Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
21. april 2022 oppdatert av: 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.
Studieoversikt
Status
Rekruttering
Forhold
Intervensjon / Behandling
Detaljert beskrivelse
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
Intervensjonell
Registrering (Forventet)
30
Fase
- Ikke aktuelt
Kontakter og plasseringer
Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.
Studiekontakt
- Navn: Long Zhao
- Telefonnummer: +18919128021
- E-post: dragonzhao@126.com
Studiesteder
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Gansu
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Lanzhou, Gansu, Kina, 730000
- Rekruttering
- The First Hospital of Lanzhou University
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Underetterforsker:
- Long Zhao
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Underetterforsker:
- Haizhen Ma
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Underetterforsker:
- Juan Cheng, MD
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Ta kontakt med:
- Long Zhao
- Telefonnummer: +18919128021
- E-post: zhaodragon@126.com
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Hovedetterforsker:
- Bei Liu, MD
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Underetterforsker:
- Jinli Jian
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Underetterforsker:
- Hao Zhang
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Deltakelseskriterier
Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
18 år og eldre (Voksen, Eldre voksen)
Tar imot friske frivillige
Nei
Kjønn som er kvalifisert for studier
Alle
Beskrivelse
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.
Studieplan
Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Enkelt
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
|---|---|
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Eksperimentell: 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.
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Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
dasatinib,20mg,po,qd,treatment cycles every 28 days
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Aktiv komparator: 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.
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Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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overall survival
Tidsramme: up to 30 months.
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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
Tidsramme: 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.
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up to 30 months.
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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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mortality
Tidsramme: mortality rate at 30 months.
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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
Tidsramme: recurrence rate at 30 months.
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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
Tidsramme: 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
Tidsramme: 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.
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once before enrollment and once after the completion of the study, up to 30 months.
|
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DNA methyltransferase, tumor suppressor genes and differentiation genes
Tidsramme: 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.
Tidsramme: 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
Tidsramme: 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.
|
Samarbeidspartnere og etterforskere
Det er her du vil finne personer og organisasjoner som er involvert i denne studien.
Sponsor
Samarbeidspartnere
Publikasjoner og nyttige lenker
Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.
Generelle publikasjoner
- 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.
Studierekorddatoer
Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.
Studer hoveddatoer
Studiestart (Faktiske)
13. november 2021
Primær fullføring (Forventet)
1. september 2023
Studiet fullført (Forventet)
15. desember 2023
Datoer for studieregistrering
Først innsendt
1. september 2021
Først innsendt som oppfylte QC-kriteriene
6. september 2021
Først lagt ut (Faktiske)
13. september 2021
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
25. april 2022
Siste oppdatering sendt inn som oppfylte QC-kriteriene
21. april 2022
Sist bekreftet
1. april 2022
Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- AZALDDASA3
- ChiCTR2100042418 (Registeridentifikator: Chinese Clinical Trial Registry)
Plan for individuelle deltakerdata (IPD)
Planlegger du å dele individuelle deltakerdata (IPD)?
NEI
IPD-planbeskrivelse
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.
Legemiddel- og utstyrsinformasjon, studiedokumenter
Studerer et amerikansk FDA-regulert medikamentprodukt
Nei
Studerer et amerikansk FDA-regulert enhetsprodukt
Nei
Denne informasjonen ble hentet direkte fra nettstedet clinicaltrials.gov uten noen endringer. Hvis du har noen forespørsler om å endre, fjerne eller oppdatere studiedetaljene dine, vennligst kontakt register@clinicaltrials.gov. Så snart en endring er implementert på clinicaltrials.gov, vil denne også bli oppdatert automatisk på nettstedet vårt. .