Decitabine,Cytarabine and Arsenic Trioxide for Acute Myeloid Leukemia With p53 Mutations
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|ClinicalTrials.gov Identifier: NCT03381781|
Recruitment Status : Unknown
Verified January 2018 by Li Junmin, Ruijin Hospital.
Recruitment status was: Not yet recruiting
First Posted : December 22, 2017
Last Update Posted : January 4, 2018
This is a prospective,uncontrolled and multi-institution trial.The aim is to identify if using decitabine,cytarabine and ATO as the therapy of acute myeloid leukemia(AML) with p53 mutations has better relapse free survival and complete response than using decitabine and cytarabine.
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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.
|Condition or disease||Intervention/treatment||Phase|
|Acute Myeloid Leukemia P53 Mutation||Drug: Decitabine Drug: Arsenic Trioxide Drug: Cytarabine||Phase 2|
This study is designed as a model of precision medicine. About 1500 AML patients will be applied for TP53 sequencing. The bone marrow samples will be collected and its p53 status will be Sanger sequenced in 3-5 days before drug administration. The 100 mp53-positive patients will be trialed, while the others (mp53-negative patients) will be subjected to standard treatment or other clinical trials.
In this study,100 patients with p53 mutations will be enrolled,including newly diagnosed AML aged 60-75,AML transferred from Myelodysplastic Syndrome(MDS) and therapy related AML.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Decitabine,Cytarabine(Ara-C) and Arsenic Trioxide(ATO) in the Treatment of Acute Myeloid Leukemia With p53 Mutations|
|Estimated Study Start Date :||March 2018|
|Estimated Primary Completion Date :||November 2019|
|Estimated Study Completion Date :||November 2020|
Experimental: Experimental group
Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
20mg/m^2,d1-5,ivgtt,28days as a duration
Drug: Arsenic Trioxide
0.16mg/kg,d1-5,ivgtt,28days as a duration
- relapse free survival [ Time Frame: From date of complete release until the date of first documented relapse, assessed up to 6-8months ]since a patient first being determined as complete release until relapse
- complete release [ Time Frame: 2-4 months since the first cycle of treatment ]the percent of patients with complete release in all patients enrolled
- overall survival [ Time Frame: primary estimated for 1year ]from first diagnosed to death whichever the cause is
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03381781
|Contact: Li Junmin, MD||0086-21-64370045 ext firstname.lastname@example.org|
|Ruijin Hospital North|
|Contact: Sujiang Zhang, MD 0086-21-67888761 email@example.com|
|Principal Investigator: Sujiang Zhang, MD|
|Contact: Junmin Li 021-86-64370045 ext 665251 firstname.lastname@example.org|
|Principal Investigator: Junming Li|
|Shanghai Institute of Hematology|
|Contact: Min Lu, Ph.D. 86-21-64370045 ext 610805 email@example.com|
|Principal Investigator: Min Lu, Ph.D.|
|Principal Investigator:||Zhang Sujiang||Shanghai Ruijin Hospital North|
|Principal Investigator:||Lu Min||Shanghai institute of Hematology|