Trial | NCT03377725  Report issue

Title

Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)
Decitabine and Arsenic Trioxide(ATO) in the Treatment of Myelodysplasic Syndrome

  • Phase

    Phase 3

  • Study Type

    Interventional

  • Status

    Withdrawn

  • Study Participants

    0
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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.
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.
Study Started
Mar 20
2018
Primary Completion
Mar 31
2018
Study Completion
Mar 31
2018
Last Update
Aug 16
2023

Drug Decitabine

20mg/m^2,d1-5,ivgtt,28days as a duration

  • Other names: DNA demethylation agent, DNA damaging agent

Drug Arsenic Trioxide

0.16mg/kg,d1-5,ivgtt,28days as a duration

  • Other names: As2O3, Arsenic

Experimental group Experimental

MDS patients of the experimental group will be treated with decitabine and arsenic trioxide.

Controlled group Active Comparator

MDS patients of the controlled group will be treated with decitabine alone.

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
No Results Posted