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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
Information provided by (Responsible Party):
Li Junmin, Ruijin Hospital

Brief Summary:

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Arm Intervention/treatment
Experimental: Experimental group
Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
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

Drug: Cytarabine
15mg/m^2,hypodermic injection,q12h,d1-7
Other Names:
  • DNA damaging agent
  • Ara-C

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. complete release [ Time Frame: 2-4 months since the first cycle of treatment ]
    the percent of patients with complete release in all patients enrolled

  2. overall survival [ Time Frame: primary estimated for 1year ]
    from first diagnosed to death whichever the cause is

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • de novo elderly AML,AML transferred from MDS,therapy related AML
  • exclude acute promyelocytic leukemia(APL)
  • p53 mutations determined by DNA sequencing from bone marrow
  • ECOG<3,CCI≤1,ADL≥100
  • bone marrow is active
  • normal hepatic function and renal function
  • normal cardiac function
  • obtain informed consent

Exclusion Criteria:

  • APL
  • without p53 mutations
  • previously treated elderly AML
  • central nervous system is involved
  • 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

Information from the National Library of Medicine

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

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Contact: Li Junmin, MD 0086-21-64370045 ext 665251 drlijunmin@126.com

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Ruijin Hospital North
Shanghai, China
Contact: Sujiang Zhang, MD    0086-21-67888761    zbruce.zhang@hotmail.com   
Principal Investigator: Sujiang Zhang, MD         
Ruijin Hospital
Shanghai, China
Contact: Junmin Li    021-86-64370045 ext 665251    drlijunming@126.com   
Principal Investigator: Junming Li         
Shanghai Institute of Hematology
Shanghai, China
Contact: Min Lu, Ph.D.    86-21-64370045 ext 610805    min.lu@shsmu.edu.cn   
Principal Investigator: Min Lu, Ph.D.         
Sponsors and Collaborators
Li Junmin
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Principal Investigator: Zhang Sujiang Shanghai Ruijin Hospital North
Principal Investigator: Lu Min Shanghai institute of Hematology

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Responsible Party: Li Junmin, director of the hematology department, Ruijin Hospital
ClinicalTrials.gov Identifier: NCT03381781    
Other Study ID Numbers: RuijinH mutant p53 AML
First Posted: December 22, 2017    Key Record Dates
Last Update Posted: January 4, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Li Junmin, Ruijin Hospital:
p53 mutation
acute myeloid leukemia
Arsenic trioxide
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Arsenic Trioxide
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors