Decitabine,Cytarabine and Arsenic Trioxide for Acute Myeloid Leukemia With p53 Mutations

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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

Detailed Description
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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.

Official Title
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Decitabine,Cytarabine(Ara-C) and Arsenic Trioxide(ATO) in the Treatment of Acute Myeloid Leukemia With p53 Mutations

Conditions
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Acute Myeloid Leukemia, P53 Mutation

Intervention / Treatment
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* Drug: Decitabine
* Drug: Arsenic Trioxide
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine. | Drug: Decitabine<br>* 20mg/m^2,d1-5,ivgtt,28days as a duration<br>* Other names: DNA damaging agent;Drug: Arsenic Trioxide<br>* 0.16mg/kg,d1-5,ivgtt,28days as a duration<br>* Other names: Arsenic;Drug: Cytarabine<br>* 15mg/m^2,hypodermic injection,q12h,d1-7<br>* Other names: Ara-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| relapse free survival | since a patient first being determined as complete release until relapse | From date of complete release until the date of first documented relapse, assessed up to 6-8months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete release | the percent of patients with complete release in all patients enrolled | 2-4 months since the first cycle of treatment | 
| overall survival | from first diagnosed to death whichever the cause is | primary estimated for 1year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia, decitabine, Arsenic trioxide, cytarabine, p53 mutation