Clinical Trials /

Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)

NCT03377725

Description:

This is a prospective,controlled and multi-institution trial.The aim is to identify if using decitabine and Arsenic Trioxide(ATO) as the therapy of Myelodysplastic Syndrome(MDS) has better relapse free survival and complete response than using decitabine alone. TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients. Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH, 2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed quickly. Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment. ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC, 1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014); Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53 subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled. We designate trials aiming for a better treatment regimen for mp53 patients as 'PANDA-Trials'.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)
  • Official Title: Decitabine and Arsenic Trioxide(ATO) in the Treatment of Myelodysplasic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: RuijinH mutant p53 MDS
  • NCT ID: NCT03377725

Conditions

  • Myelodysplastic Syndromes
  • P53 Mutation

Interventions

DrugSynonymsArms
DecitabineDNA demethylation agent, DNA damaging agentExperimental group
Arsenic TrioxideAs2O3, ArsenicExperimental group

Purpose

This is a prospective,controlled and multi-institution trial.The aim is to identify if using decitabine and Arsenic Trioxide(ATO) as the therapy of Myelodysplastic Syndrome(MDS) has better relapse free survival and complete response than using decitabine alone. TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients. Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH, 2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed quickly. Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment. ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC, 1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014); Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53 subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled. We designate trials aiming for a better treatment regimen for mp53 patients as 'PANDA-Trials'.

Detailed Description

      300 MDS patients will be recruited for trial. They will be randomly administrated with ATO +
      decitabine (n=200) or decitabine alone (n=100). The RSF, CR ratio, overall survival will be
      compared between the two arms. Importantly, TP53 status will be sequenced and its correlation
      with RSF, CR ratio, overall survival within the two arms will be investigated.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental groupExperimentalMDS patients of the experimental group will be treated with decitabine and arsenic trioxide.
  • Decitabine
  • Arsenic Trioxide
Controlled groupActive ComparatorMDS patients of the controlled group will be treated with decitabine alone.
  • Decitabine

Eligibility Criteria

        Inclusion Criteria:

          -  de novo MDS

          -  The Revised International Prognostic Scoring System(IPSS-R) is intermediate,poor or
             very poor

          -  18-75years old(including 18-year-old and 75-year-old patients)

          -  ECOG<3,CCI≤1,ADL≥100

          -  bone marrow is active

          -  normal hepatic function and renal function

          -  normal cardiac function

          -  obtain informed consent

        Exclusion Criteria:

          -  previously treated MDS patients

          -  abnormal hepatic function or renal function

          -  severe cardiac disease,including myocardial infarction,cardiac dysfunction

          -  ECG:QTc>0.44 sec in men,QTc>0.46 sec in women

          -  with other malignant tumor meanwhile

          -  active tuberculosis or HIV-positive patients

          -  woman who are pregnant or breastfeeding

          -  allergic to any drug in protocol or with contraindications

          -  hypomethylation agent(HMA) is contraindicated

          -  ECOG≥3,CCI>1,ADL<100

          -  cannot understand or obey the protocol

          -  with a history of allergies or intolerability

          -  with a history of decitabine therapy

          -  participate in other clinical trials meanwhile

          -  any situations that hinder trial existed
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:relapse free survival
Time Frame:up to 6-8 months after complete release
Safety Issue:
Description:since a patient first being determined as complete release until relapse

Secondary Outcome Measures

Measure:complete release
Time Frame:2-4 months since the first cycle of treatment
Safety Issue:
Description:the percent of patients with complete release in all patients enrolled
Measure:overall survival
Time Frame:primary estimated for 1year
Safety Issue:
Description:from first diagnosed to death whichever the cause is

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Li Junmin

Trial Keywords

  • Myelodysplastic Syndromes
  • Decitabine
  • Arsenic Trioxide
  • P53 Mutations

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