Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)

Study Overview
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Brief Summary
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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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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
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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.

Official Title
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Decitabine and Arsenic Trioxide(ATO) in the Treatment of Myelodysplasic Syndrome

Conditions
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Myelodysplastic Syndromes, P53 Mutation

Intervention / Treatment
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* Drug: Decitabine
* Drug: Arsenic Trioxide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>MDS patients of the experimental group will be treated with decitabine and arsenic trioxide. | Drug: Decitabine<br>* 20mg/m^2,d1-5,ivgtt,28days as a duration<br>* Other names: DNA damaging agent;Drug: Arsenic Trioxide<br>* 0.16mg/kg,d1-5,ivgtt,28days as a duration<br>* Other names: Arsenic;|
| Active Comparator: Controlled group<br>MDS patients of the controlled group will be treated with decitabine alone. | Drug: Decitabine<br>* 20mg/m^2,d1-5,ivgtt,28days as a duration<br>* Other names: DNA damaging agent;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndromes, Decitabine, Arsenic Trioxide, P53 Mutations