Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)
- Conditions
- Myelodysplastic SyndromesP53 Mutation
- Interventions
- Registration Number
- NCT03377725
- Lead Sponsor
- Li Junmin
- Brief Summary
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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Experimental group Arsenic Trioxide MDS patients of the experimental group will be treated with decitabine and arsenic trioxide. Experimental group Decitabine MDS patients of the experimental group will be treated with decitabine and arsenic trioxide. Controlled group Decitabine MDS patients of the controlled group will be treated with decitabine alone.
- Primary Outcome Measures
Name Time Method relapse free survival up to 6-8 months after complete release since a patient first being determined as complete release until relapse
- Secondary Outcome Measures
Name Time Method overall survival primary estimated for 1year from first diagnosed to death whichever the cause is
complete release 2-4 months since the first cycle of treatment the percent of patients with complete release in all patients enrolled
Trial Locations
- Locations (3)
Ruijin Hospital North
🇨🇳Shanghai, China
Ruijin Hospital
🇨🇳Shanghai, China
Shanghai Institute of Hematology
🇨🇳Shanghai, China