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unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via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Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of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'.
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
Drug | Synonyms | Arms |
---|
Decitabine | DNA demethylation agent, DNA damaging agent | Controlled group |
Arsenic Trioxide | As2O3, Arsenic | Experimental 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
Name | Type | Description | Interventions |
---|
Experimental group | Experimental | MDS patients of the experimental group will be treated with decitabine and arsenic trioxide. | - Decitabine
- Arsenic Trioxide
|
Controlled group | Active Comparator | MDS patients of the controlled group will be treated with decitabine alone. | |
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: | Unknown status |
Lead Sponsor: | Li Junmin |
Trial Keywords
- Myelodysplastic Syndromes
- Decitabine
- Arsenic Trioxide
- P53 Mutations
Last Updated
January 4, 2018